Artículos de revistas: "Hematopoietic growth factors Therapeutic use"

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Costa, John J. "The therapeutic use of hematopoietic growth factors". Journal of Allergy and Clinical Immunology 101, n.º 1 (enero de 1998): 1–6. http://dx.doi.org/10.1016/s0091-6749(98)70185-x.

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2

Sola, Martha y Robert D. Christensen. "Use of Hematopoietic Growth Factors in the Neonatal Intensive Care Unit". Journal of Intensive Care Medicine 12, n.º 4 (julio de 1997): 187–205. http://dx.doi.org/10.1177/088506669701200403.

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Recombinant hematopoietic growth factors have emerged as valuable treatments for a variety of medical conditions. Recently, their applications have reached the neonatal intensive care unit, where they offer new therapeutic options for problems as common as anemia of prematurity, or as catastrophic as neonatal sepsis. When facing bacterial infection, it is known that newborn infants are capable of increasing their serum G-CSF concentrations. However, their response does not reach the concentrations that adults are able to achieve, and frequently neutropenia complicates the picture of neonatal sepsis. Although Phase III clinical trials are still in progress, published animal studies, case reports, and Phase I trials suggest that neonates with a variety of neutropenias experience a rapid elevation in their blood neutrophil concentration following administration of rG-CSF, without significant adverse effects. Although many factors contribute to the development of the “anemia of prematurity,” one of the major factors is the inability of preterm infants to generate an erythropoietin (Epo) response appropriate to their degree of anemia. On the basis of this fact, administration of rEpo to preterm neonates to treat or to prevent the anemia of prematurity has been the subject of multiple clinical studies, and it is now clear that rEpo administration to this population can indeed result in lower transfusion requirements, with only occasional and mild adverse effects. Neonatal thrombocytopenia is also a frequent clinical problem, which in most patients develops without a clear underlying cause. Recent studies, quantifying circulating megakaryocyte progenitors in the peripheral blood of thrombocytopenic neonates, suggest that impaired megakaryocytopoiesis may be the main underlying mechanism of many cases of thrombocytopenia. On the basis of this finding, it is tempting to speculate that recombinant thrombopoietin, the newly discovered physiological stimulator of platelet production, will be of clinical relevance in the treatment of thrombocytopenic neonates.

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Bossi, Paolo, Cristina Gurizzan, Luigi Lorini, Pierluigi di Mauro, Chiara Sardini y Marco Merlano. "Not all hematopoietic growth factors are created equal: should we gain information for their use with immunotherapy?" Journal for ImmunoTherapy of Cancer 9, n.º 8 (agosto de 2021): e003154. http://dx.doi.org/10.1136/jitc-2021-003154.

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Myeloid growth factors, either granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF, are widely used to reduce the incidence and severity of chemotherapy-induced neutropenia by prophylactic or therapeutic administration. However, their activity in the novel therapeutic regimens, which often rely on the association between immunotherapy and chemotherapy, has not been thoroughly characterized yet. This paper presents some of the preclinical and clinical research regarding the putative interplay between myeloid growth factors and the immune system, advocating further studies to elucidate their potential positive or negative consequences on the outcomes when administered with immunotherapeutic agents.

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4

Bridges, Sandra H., Margaret I. Johnston y John J. McGowan. "Immunosuppression and HIV Infection: A Therapeutic Challenge". Canadian Journal of Infectious Diseases 3, suppl b (1992): 55–59. http://dx.doi.org/10.1155/1992/740587.

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The optimal use of biological response modifiers (BRMs) in human immunodeficiency virus (HIV)-related disease depends on knowledge of the molecular basis of the immune deficiencies and dysregulations that occur during the course of the infection; evidence for the role of viral products and cytokines in the suppression of immune function is discussed. Immunebased therapies are currently being explored alone and in combination with drugs targeted to HIV and associated opportunistic infections and malignancies. These therapies include hematopoietic growth factors for the management of drug toxicities, cytokines, antigen- and cell-based therapies, and synthetic immunomodulators. The entry of additional BRMs into clinical trials for HIV-disease can be facilitated by well-designed preclinical studies that address special problems related to the disease. including the need for concomitant therapy for the spectrum of disease manifestations encountered.

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Siena, Salvatore, Roberta Schiavo, Paolo Pedrazzoli y Carmelo Carlo-Stella. "Therapeutic Relevance of CD34 Cell Dose in Blood Cell Transplantation for Cancer Therapy". Journal of Clinical Oncology 18, n.º 6 (13 de marzo de 2000): 1360–77. http://dx.doi.org/10.1200/jco.2000.18.6.1360.

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PURPOSE: To review recent advances in peripheral-blood progenitor-cell (PBPC) transplantation in order to define the optimal cell dose required for autologous and allogeneic transplantation. MATERIALS AND METHODS: A search of MEDLINE was conducted to identify relevant publications. Their bibliographies were also used to identify further articles and abstracts for critical review. RESULTS: The CD34+ cell content of a graft is regarded as an accurate predictor of engraftment success. Postchemotherapy autologous PBPC transplantation with ≥ 5 × 106 CD34+ cells/kg body weight leads to more rapid engraftment than does transplantation of lower cell doses. Further increases in transplant cell dose further accelerate platelet but not neutrophil engraftment. Evidence that long-term hematopoietic recovery may be more accurately predicted by the subpopulation of primitive progenitors transplanted suggests that the content of CD34+CD33− and long-term culture-initiating cells in cell collection samples may be important for predicting successful engraftment, particularly in patients with poor mobilization. Allogeneic transplantation has been limited by concerns regarding graft-versus-host disease and the use of hematopoietic growth factors in donors. The risk of graft rejection and engraftment failure after HLA-mismatched allogeneic transplantation may be overcome by intensive chemoradiotherapy and the infusion of large numbers of T cell–depleted hematopoietic stem cells. CONCLUSION: An optimal cell dose of ≥ 8 × 106 CD34+ cells/kg seems to be recommended for autologous PBPC transplantation. This dose facilitates the administration of scheduled chemotherapy on time and reduces the demand for other supportive therapies. A combination of growth factors may enable patients with poor mobilization to achieve a collection sufficient to allow transplantation. The optimum PBPC dose for allogeneic transplantation remains to be defined.

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6

Zhao, Q., X. Song, T. Waldschmidt, E. Fisher y AM Krieg. "Oligonucleotide uptake in human hematopoietic cells is increased in leukemia and is related to cellular activation". Blood 88, n.º 5 (1 de septiembre de 1996): 1788–95. http://dx.doi.org/10.1182/blood.v88.5.1788.1788.

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Abstract The use of antisense oligonucleotides as tools for modulating gene expression represents a novel strategy for designing drugs to treat a variety of diseases. Several factors, including cellular uptake and internalization of the oligonucleotides, are important parameters in determining the effectiveness of antisense agents such as therapeutic drugs. We have studied oligonucleotides uptake in normal and leukemic human hematopoietic cells, such as peripheral blood, bone marrow (BM), and HL-60 cell line; and have found that, in normal human blood and BM, myeloid cells and B cells preferably took up more oligonucleotides than T cells. There was no marked difference in oligonucleotide uptake between CD4+ helper T cells and CD8+ cytolytic T cells. Leukemic cells had greater oligonucleotide uptake than their normal counterparts. Furthermore, oligonucleotide uptake was closely related to cell activation status and can be modulated by growth factors or inhibitors. These studies provide a basis for using oligonucleotides as therapeutic drugs both in vitro and in vivo.

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7

Zhao, Q., X. Song, T. Waldschmidt, E. Fisher y AM Krieg. "Oligonucleotide uptake in human hematopoietic cells is increased in leukemia and is related to cellular activation". Blood 88, n.º 5 (1 de septiembre de 1996): 1788–95. http://dx.doi.org/10.1182/blood.v88.5.1788.bloodjournal8851788.

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The use of antisense oligonucleotides as tools for modulating gene expression represents a novel strategy for designing drugs to treat a variety of diseases. Several factors, including cellular uptake and internalization of the oligonucleotides, are important parameters in determining the effectiveness of antisense agents such as therapeutic drugs. We have studied oligonucleotides uptake in normal and leukemic human hematopoietic cells, such as peripheral blood, bone marrow (BM), and HL-60 cell line; and have found that, in normal human blood and BM, myeloid cells and B cells preferably took up more oligonucleotides than T cells. There was no marked difference in oligonucleotide uptake between CD4+ helper T cells and CD8+ cytolytic T cells. Leukemic cells had greater oligonucleotide uptake than their normal counterparts. Furthermore, oligonucleotide uptake was closely related to cell activation status and can be modulated by growth factors or inhibitors. These studies provide a basis for using oligonucleotides as therapeutic drugs both in vitro and in vivo.

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8

Thaker, Hatim y Arun K. Sharma. "Engaging Stem Cells for Customized Tendon Regeneration". Stem Cells International 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/309187.

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The need for a consistent therapeutic approach to tendon injury repair is long overdue. Patients with tendon microtears or full ruptures are eligible for a wide range of invasive and non invasive interventions, often subjectively decided by the physician. Surgery produces the best outcomes, and while studies have been conducted to optimize graft constructs and to track outcomes, the data from these studies have been inconclusive on the whole. What has been established is a clear understanding of healthy tendon architecture and the inherent process of healing. With this knowledge, tissue regeneration efforts have achieved immense progress in scaffold design, cell line selection, and, more recently, the appropriate use of cytokines and growth factors. This paper evaluates the plasticity of bone-marrow-derived stem cells and the elasticity of recently developed biomaterials towards tendon regeneration efforts. Mesenchymal stem cells (MSCs), hematopoietic progenitor cells, and poly(1,8-octanediol co-citrate) scaffolds (POC) are discussed in the context of established grafting strategies. With POC scaffolds to cradle the growth of MSCs and hematopoietic progenitor cells, developing a fibroelastic network guided by cytokines and growth factors may contribute towards consistent graft constructs, enhanced functionality, and better patient outcomes.

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9

Mohindru, Mani, Perry Pahanish, Efstratios Katsoulidis, Robert Collins, Thomas Rogers, Tony Navas, Linda Higgins, Leonidas Platanias y Amit Verma. "Novel P38 MAP Kinase Inhibitor and Anti-P38 RNA Interference as Potential Therapeutic Approaches in Myelodysplastic Syndromes." Blood 104, n.º 11 (16 de noviembre de 2004): 470. http://dx.doi.org/10.1182/blood.v104.11.470.470.

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Abstract Cytokines such as TNF α, IFN γ and others have been implicated in the pathogenesis of ineffective hematopoiesis in MDS and are thought to lead to the high rate of apoptosis in hematopoietic progenitors. The p38 Mitogen Activated Protein Kinase (MAPK) is an evolutionary conserved enzyme that is involved in many cellular processes including stress signaling. We have previously shown that the p38 MAP kinase is strongly activated by IFNs, TNF α, TGF β and other inhibitory cytokines in normal primary hematopoietic progenitors and plays an important role in the negative regulation of normal hematopoiesis. In the present study, we determined the role of the p38 MAPK in the pathogenesis of MDS evaluated its inhibition as a potential therapeutic strategy in this disease. p38 MAPK inhibition was achieved by the use of a novel p38 inhibitor - SD-282, a specific inhibitor of p38α MAP kinase. SD-282 performs very similarly in animal and cell models to a p38 inhibitor now in the clinic. We also transfected primary hematopoietic cells with flurescent labeled siRNAs against p38 and successfully downregulated the levels of the protein. Using these approaches, we demonstrate that pharmacological inhibition of the p38 MAPK can reverse the growth inhibitory effects of TNF α and IFN γ on erythroid and myeloid colony formation. This reversal of TNF α mediated inhibition correlates with significant reduction of apoptosis seen in human hematopoeitic progenitors pretreated with p38 inhibitor SD-282. Having established the importance of p38 MAPK in cytokine mediated inhibition of normal hematopoiesis, we performed colony forming assays with bone marrow CD34+ cells from 8 patients with MDS in the presence of either pharmacologic or siRNA based inhibitors of p38. All patients had refractory cytopenias with multilineage dysplasia. Our data indicates that SD-282 treatment strongly enhances both erythroid and myeloid colony formation in MDS CD34+ bone marrow cells in vitro. This increase was not observed when these progenitors were grown in the presence of negative controls - SB 202474 and the MEK inhibitor PD 98059. Similarly, an increase in hematopoietic colony formation, though of a lesser magnitude was seen when MDS bone marrow progenitors were transfected with siRNAs against p38 MAPK. To further determine the role of cytokines in the pathogenesis of MDS, we also used bone marrow derived sera from the same MDS patients. Our studies show exposure to patient derived sera led to the phosphorylation/activation of p38 MAPK in normal hematopoietic progenitors when compared to sera from healthy volunteers. Our studies also demonstrate that bone marrow derived sera from MDS patients can inhibit erythroid and myeloid colony formation of normal hematopoietic progenitors. This inhibition can be reversed by blocking p38 MAPK using SD-282, other p38 inhibitors and siRNAs. This finding confirms the role of marrow cytokine /serum factors in the ineffective hematopoiesis seen in MDS and suggests the importance of p38 MAPK activation in this phenomenon. Thus our studies show the p38 MAPK may be a common effector of inhibitory cytokine signaling in normal and MDS hematopoietic cells. These results provide a strong rationale for using p38 inhibition as a novel treatment strategy for MDS. Supported by Harris Methodist Foundation Grant, VISN-17 New Investigator Grant and VA Research Corp Grant to AV.

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Or, Reuven, Sigal Grisaro, Batia Ronit Avni, Igor Resnick, Lilyan Dari, David Shoshani, Dalia Bracha, Nurit Beilin, Limor Lior y Michael Y. Shapira. "Correction of Post-Transplant Hematopoiesis by Novel Use of Mesenchymal-Like Placental Expanded Cells (PLX) Administered Intra-Muscular". Blood 120, n.º 21 (16 de noviembre de 2012): 4133. http://dx.doi.org/10.1182/blood.v120.21.4133.4133.

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Abstract Abstract 4133 Post autologous or allogeneic stem cell transplantation hematopoietic dysfunction is a common phenomenon caused by multiple factors. Complicating the treatment of this condition is the fact that additional reserves of stem cells for autologous transplantation is usually unavailable and the use of allogeneic stem cells, if available, may be associated with transplant related complications, including graft versus host disease. Furthermore, the addition of donor cells may be ineffective because the underlying disease may also damage the supplemented stem cells. Prolonged pancytopenia in cases not responding to hematopoietic growth factors is a major life threatening condition. Bone marrow derived mesenchymal stem cells (MSC) are multi-potent cell that are being clinically explored as immune modulators and inducers of stem cell plasticity. Placental-expanded (PLX) cells are mesenchymal-like adherent stromal cells derived from the full term placenta. The cells are expanded in a bioreactor system, which provides a three dimensional microenvironment for cell growth. This system enables full control over the manufacturing process, large-scale growth of these cells and batch-to-batch consistency. PLX cells are immune privileged and suitable for allogeneic administration without HLA-Matching. Additionally, PLX cells are known to secrete a wide range of anti-inflammatory cytokines as well as various growth factors. Three patients suffered from severe and long-standing pancytopenia with associated complications after receiving hematopoietic stem cell transplantations (two allogeneic and one autologous). They were treated on a compassionated basis with intra-muscular (IM) injections of PLX cells in an attempt to enhance hematopoiesis. The first case was a 7 year-old girl that suffered from severe aplastic anemia and underwent two un-manipulated allogeneic stem cell transplantations from two different unrelated donors. The second patient was a 55 year-old woman that suffered from non-Hodgkin lymphoma and sustained an autologous stem cell transplantation. The third patient was a 45 year-old male with AML that underwent an allogeneic, un-manipulated transplant from an unrelated source. On days 74, 46, 144 post-transplant respectively for each patient, PLX cells were injected IM at a dose of 600×106 cells per adult and 160×106cell per child, divided in two administrations one week apart. No local or systemic side effects were observed. All three patients had impressive clinical improvement, which enabled them to be discharged from the hospital. The first 2 patients responded 4 and 9 days respectively after the second PLX cell administration, with improvement of tri-linage hematopoiesis. The third patient became significantly less transfusion dependent. PLX cell's immunomodulatory properties and cytokine secretory potential might be involved in the bone marrow regeneration capacity seen in these patients. The endocrine mode of action following the IM administration of PLX cells is a new and simple concept for cell therapy. Future clinical trials are needed to investigate the potential of PLX cells to enhance and shorten bone marrow engraftment following autologous or allogeneic bone marrow transplantation. Disclosures: Shoshani: Pluristem Therapeutics Inc., Haifa, Israel: Employment. Bracha:Pluristem Therapeutics Inc., Haifa, Israel: Employment. Beilin:Pluristem Therapeutics Inc., Haifa, Israel: Employment. Lior:Pluristem Therapeutics Inc., Haifa, Israel: Employment.

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Coman, Tereza, Guillemette Fouquet, Julien Rossignol, Jean-Henri Bourhis, Olivier Hermine y Francine Côté. "Serotonin Targeting Using Common Antidepressants Induces Rapid Recovery of Cytopenia". Blood 134, Supplement_1 (13 de noviembre de 2019): 3715. http://dx.doi.org/10.1182/blood-2019-122658.

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Background. Hematopoiesis is a highly regulated system where multiple, yet undiscovered, factors orchestrate the self-renewal of bone marrow stem cells and their differentiation into blood cells. Following acute stresses like infections, inflammation, chemotherapy or radiation, the hematopoietic system quickly adapts by a process termed "emergency" or "stress" hematopoiesis. For instance, switches from steady state to emergency granulopoiesis or emergency erythropoiesis have been described in response to infection or bleeding. We recently identified, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. Furthermore, pharmacologic restoration of serotonin levels using selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, a common antidepressant, was demonstrated to rescue the anemic phenotype in mice models. Here, we hypothesized that serotonin also has a role on other hematopoietic lineages, and that the serotonergic system could be a valuable therapeutic target in radiation or chemotherapy-induced cytopenia. Moreover, as our previous work suggested a cross-talk between serotonin and erythropoietin, we postulate that serotonin could act in cooperation with known hematopoietic growth factors. Material and method. For mice models, we submitted C57BL/6 wild-type 8-10 weeks old mice to sub-lethal irradiation and monitored hematopoietic recovery through complete blood counts. We compared mice treated with fluoxetine administrated orally (~ 20 mg/kg/day in drinking water) to a control group, with or without hematopoietic growth factors. For the retrospective human cohort, we used a computerized database to identify patients who underwent autologous hematopoietic stem cell transplantation (ASCT) in the adult hematology department of Necker hospital between 2008 and 2018. We compared 22 patients treated with an SSRI to 66 controls, matched according to number of injected CD34+ cells/kg, age, sex, conditioning chemotherapy, pathology, depth of response before transplantation, previous lines of chemotherapy, and year of transplantation. The study was conducted according to the Declaration of Helsinki. Results. First, we confirmed that, following sub-lethal irradiation, pharmacologic restoration of 5-HT levels in mice using fluoxetine improved normalization of the erythroid lineage (at day 17 post-irradiation, mean hemoglobin was 8.1 versus 2.8 g/dL in the fluoxetine versus control group (p=0.0002)). Second, the data revealed that the use of SSRI lead to a more rapid restoration of the leukocytes and platelets levels (at day 17 post-irradiation, mean leukocyte level was 1740 versus 314/mm3 (p<0.0001) and mean platelet level was 216 versus 43/mm3 (p=0.002) in the fluoxetine versus control group, respectively). Third, we observed an additive effect between fluoxetine and Granulocyte-Colony Stimulating Factor (G-CSF) on the recovery of the three myeloid lineages (at day 17 post-irradiation, mean hemoglobin was 10.5 versus 4.0 g/dL (p<0.0001), mean leukocyte level was 2900 versus 900/mm3 (p<0.0001) and mean platelet level was 308 versus 84/mm3 (p=0.0009) in the fluoxetine + G-CSF versus control group, respectively). Finally, analysis of the in vivo murine model under steady state condition showed that without any hematopoietic stress, fluoxetine did not impact hematopoiesis. In human, analysis of the retrospective ASCT cohort demonstrated that patients treated with SSRI had a more rapid neutrophil recovery than matched control patients (mean duration of neutropenia <500/mm3 was 12.2 days in the SSRI group and 14.26 days in the control group, p=0.0216). SSRI therapy was not associated with a higher rate or quicker relapses of underlying malignant hemopathy: mean progression free survival was 36 months in both groups. Conclusion. In this work, we report a previously unknown role of SSRI in the hematopoietic recovery of cytopenia, both after sub-lethal irradiation in mice and after autologous hematopoietic stem cell transplantation in human. We also observed a significant cooperation between SSRI and G-CSF on the three myeloid lineages. We propose that the serotonergic system could be a valuable therapeutic target in stress hematopoiesis such as in therapy-induced aplasia in patients. Disclosures Hermine: AB Science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding. OffLabel Disclosure: Fluoxetine is a selective serotonin reuptake inhibitor for oral administration. It is an antidepressant approved for major depressive disorder, obsessive compulsive disorder, bulimia nervosa and panic disorder. We believe its role on serotonin can improve hematopoiesis.

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Papanikolaou, Xenofon Dimitrios, Eric Rosenbaum, Lisa Tyler, Bart Barlogie y Michele Cottler-Fox. "Factors that predict successful remobilization after autologous hematopoietic progenitor cell transplant (aHCT) for multiple myeloma." Journal of Clinical Oncology 31, n.º 15_suppl (20 de mayo de 2013): 8610. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8610.

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8610 Background: aHCT is a proven therapeutic modality in treating relapsed multiple myeloma (MM). However, previously transplanted patients may have no hematopoietic progenitor cells (HPC) left in storage. Methods: Collection of HPC after aHCT was studied in 221 MM patients who underwent 333 mobilization attempts between 10/2000 and 06/2012. Results: The median number of CD34+ collected was 4.7 ×106/kg, with 74% of collections yielding at least 2.5×106/kg. Mobilization with chemotherapy and G-CSF was most efficient, yielding a median of 6.84×106/kg (p<0.001). Growth factor-only mobilization was least effective, with a median of 3.01×106/kg (p<0.001). The addition of plerixafor yielded a significant increase if there was a previous “poor” (<2.5×106/kg) collection (1.83 vs. 3.43×106/kg, p<0.001). In univariate statistical analysis female sex (p=0.048), platelets (PLT) ≤100×106/L (p<0.001), hemoglobin ≤11g/dL (p=0.032), and albumin ≤3.5 g/dL (p=0.003) prior to mobilization correlated with a “poor” collection. In multivariate analysis only PLT ≤100×106/L was significant (p<0.001). Of the 221 patients collected, 154 underwent subsequent aHCT. Infusion of HPC procured after previous aHCT did not yield a difference in treatment-related mortality (p=0.766). Use of only cells collected after aHCT was related to a delayed platelet engraftment ≥50×106/L (p<0.001). Conclusions: Remobilization and collection of an adequate number of HPC after previous aHCT is feasible. PLT ≤100×106/L suggest the need for plerixafor for a successful collection. Infusion of the graft procured is safe and effective, but use of only cells collected after aHCT is associated with delayed platelet engraftment >50×106/L.

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Brugger, W., W. Mocklin, S. Heimfeld, RJ Berenson, R. Mertelsmann y L. Kanz. "Ex vivo expansion of enriched peripheral blood CD34+ progenitor cells by stem cell factor, interleukin-1 beta (IL-1 beta), IL-6, IL-3, interferon-gamma, and erythropoietin". Blood 81, n.º 10 (15 de mayo de 1993): 2579–84. http://dx.doi.org/10.1182/blood.v81.10.2579.2579.

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Abstract To provide sufficient numbers of peripheral blood progenitor cells (PBPCs) for repetitive use after high-dose chemotherapy, we investigated the ability of hematopoietic growth factor combinations to expand the number of clonogenic PBPCs ex vivo. Chemotherapy plus granulocyte colony-stimulating factor (G-CSF) mobilized CD34+ cells from 18 patients with metastatic solid tumors or refractory lymphomas were cultured for up to 28 days in a liquid culture system. The effects of interleukin-1 beta (IL-1), IL-3, IL-6, granulocyte-macrophage-CSF (GM-CSF), G-CSF, macrophage-CSF (M-CSF), stem cell factor (SCF), erythropoietin (EPO), leukemia inhibitory factor (LIF), and interferon- gamma, as well as 36 combinations of these factors were tested. A combination of five hematopoietic growth factors, including SCF, EPO, IL-1, IL-3, and IL-6, was identified as the optimal combination of growth factors for both the expansion of total nucleated cells as well as the expansion of clonogenic progenitor cells. Proliferation peaked at days 12 to 14, with a median 190-fold increase (range, 46- to 930- fold) of total clonogenic progenitor cells. Expanded progenitor cells generated myeloid (colony-forming unit-granulocyte-macrophage), erythroid (burst-forming unit-erythroid), as well as multilineage (colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte) colony-forming units. The number of multilineage colonies increased 250- fold (range, 33- to 589-fold) as compared with pre-expansion values. Moreover, the absolute number of early hematopoietic progenitor cells (CD34+/HLA-DR-; CD34+/CD38-), as well as the number of 4-HC-resistant progenitors within expanded cells increased significantly. Interferon- gamma was shown to synergize with the 5-factor combination, whereas the addition of GM-CSF significantly decreased the number of total clonogenic progenitor cells. Large-scale expansion of PB CD34+ cells (starting cell number, 1.5 x 10(6) CD34+ cells) in autologous plasma supplemented with the same 5-factor combination resulted in an equivalent expansion of progenitor cells as compared with the microculture system. In summary, our data indicate that chemotherapy plus G-CSF-mobilized PBPCs from cancer patients can be effectively expanded ex vivo. Moreover, our data suggest the feasibility of large- scale expansion of PBPCs, starting from small numbers of PB CD34+ cells. The number of cells expanded ex vivo might be sufficient for repetitive use after high-dose chemotherapy and might be candidate cells for therapeutic gene transfer.

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Brugger, W., W. Mocklin, S. Heimfeld, RJ Berenson, R. Mertelsmann y L. Kanz. "Ex vivo expansion of enriched peripheral blood CD34+ progenitor cells by stem cell factor, interleukin-1 beta (IL-1 beta), IL-6, IL-3, interferon-gamma, and erythropoietin". Blood 81, n.º 10 (15 de mayo de 1993): 2579–84. http://dx.doi.org/10.1182/blood.v81.10.2579.bloodjournal81102579.

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To provide sufficient numbers of peripheral blood progenitor cells (PBPCs) for repetitive use after high-dose chemotherapy, we investigated the ability of hematopoietic growth factor combinations to expand the number of clonogenic PBPCs ex vivo. Chemotherapy plus granulocyte colony-stimulating factor (G-CSF) mobilized CD34+ cells from 18 patients with metastatic solid tumors or refractory lymphomas were cultured for up to 28 days in a liquid culture system. The effects of interleukin-1 beta (IL-1), IL-3, IL-6, granulocyte-macrophage-CSF (GM-CSF), G-CSF, macrophage-CSF (M-CSF), stem cell factor (SCF), erythropoietin (EPO), leukemia inhibitory factor (LIF), and interferon- gamma, as well as 36 combinations of these factors were tested. A combination of five hematopoietic growth factors, including SCF, EPO, IL-1, IL-3, and IL-6, was identified as the optimal combination of growth factors for both the expansion of total nucleated cells as well as the expansion of clonogenic progenitor cells. Proliferation peaked at days 12 to 14, with a median 190-fold increase (range, 46- to 930- fold) of total clonogenic progenitor cells. Expanded progenitor cells generated myeloid (colony-forming unit-granulocyte-macrophage), erythroid (burst-forming unit-erythroid), as well as multilineage (colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte) colony-forming units. The number of multilineage colonies increased 250- fold (range, 33- to 589-fold) as compared with pre-expansion values. Moreover, the absolute number of early hematopoietic progenitor cells (CD34+/HLA-DR-; CD34+/CD38-), as well as the number of 4-HC-resistant progenitors within expanded cells increased significantly. Interferon- gamma was shown to synergize with the 5-factor combination, whereas the addition of GM-CSF significantly decreased the number of total clonogenic progenitor cells. Large-scale expansion of PB CD34+ cells (starting cell number, 1.5 x 10(6) CD34+ cells) in autologous plasma supplemented with the same 5-factor combination resulted in an equivalent expansion of progenitor cells as compared with the microculture system. In summary, our data indicate that chemotherapy plus G-CSF-mobilized PBPCs from cancer patients can be effectively expanded ex vivo. Moreover, our data suggest the feasibility of large- scale expansion of PBPCs, starting from small numbers of PB CD34+ cells. The number of cells expanded ex vivo might be sufficient for repetitive use after high-dose chemotherapy and might be candidate cells for therapeutic gene transfer.

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15

Melo, Adriana de, André Luiz de Melo, Maria Cristina Marcucci, Claudemir de Carvalho y Carolina Passarelli Gonçalves. "Immunomodulatory activity in tumor-bearing mice treated with Withania somnifera extract". Journal of Analytical & Pharmaceutical Research 10, n.º 2 (12 de abril de 2021): 82–91. http://dx.doi.org/10.15406/japlr.2021.10.00369.

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We investigated some actions of Withania somnifera on the growth and differentiation of hematopoietic precursors [granulocyte/macrophage colony cell formation (CFU-GM)] of normal animals and EAT bearers, which were treated with different doses (20, 50, or 100 mg/kg/day). We also evaluated the presence of colony stimulatory factors in the animal's serum, as well as its survival. Furthermore, we analyzed lymphocyte proliferation, IFN-ɤ, and TNF-α concentrations in treated bearing mice. Our results demonstrated Withania somnifera effectiveness on hematopoietic precursors growth and differentiation in marrow and spleen TAE-bearing mice. As it was already expected, EAT produced myelosuppression and increased CFU-GM spleen number concomitantly. The treatment of EAT-bearing animals with W.S. (20, 50, and 100 mg/Kg) produced a dose-dependent increase in myelopoiesis, an increase in a lifetime, and a reduction in spleen colony number. All this happened parallel to survival. As to lymphocyte proliferation, they were also dose-dependent in treated bearing animals. Concerning IFN-γ levels, we observed a significant reduction in non-treated bearing mice. Levels of TNF-α of treated bearing mice significantly increased when compared to the non-treated bearing group. These results are encouraging since they favor the use of W.S. extract in therapeutic combinations with other chemotherapeutic agents to reduce myelotoxicity and supplement the tumoricidal efficacy of this plant.

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Haritwal, Teena, Noopur Gupta, Mrinalini Tiwari, Sarvesh Surve y Paban Kumar Agrawala. "Radiation Countermeasures: Current Status". Defence Life Science Journal 2, n.º 3 (3 de agosto de 2017): 278. http://dx.doi.org/10.14429/dlsj.2.11675.

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Deleterious effects of ionising radiation leading to significant morbidity and mortality have been studied elaborately. A range of synthetic, semisynthetic and herbal compounds have been screened as radiation countermeasure agents and a number of promising radiation countermeasure agents are under development. Amifostin is the only drug which has been approved by the United State Food and Drug Administration (US-FDA), but that too for use in a defined population under strict medical supervision. Granulocyte Colony Stimulating Factor/filgrastim, γ-tocotrienol, genistein are at an advanced stage of development and are tested on higher animal models as per required norms of FDA. Herbal compounds are also considered very safe and of high value as radiation countermeasure agents owing to various properties like antioxidant, immunomodulation activity etc. Histone deacetylase inhibitors such as Trichostatin A, Diallyl sulphide, Sulforaphane are being viewed as very promising radiomitigating agents by our laboratory and active research in the same direction is going on. Infusion of hematopoietic stem cells and growth factors are in practice as potent therapeutics. This review gives an overview on various radioprotectors, radiomitigators and therapeutic agents either available or under development currently.

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Logothetis, C. J., L. D. Finn, T. Smith, R. G. Kilbourn, J. A. Ellerhorst, A. A. Zukiwski, A. Sella, S. M. Tu y R. J. Amato. "Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial." Journal of Clinical Oncology 13, n.º 9 (septiembre de 1995): 2272–77. http://dx.doi.org/10.1200/jco.1995.13.9.2272.

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PURPOSE Hematopoietic growth factors have been shown to ameliorate the side effects of chemotherapy. Here we assess the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to increase the dose-intensity and reduce the side effects of escalated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. PATIENTS AND METHODS A prospective randomized trial to compare escalated MVAC versus escalated MVAC with rhGM-CSF was conducted. All patients were treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) and had a metastatic or unresectable urothelial tumor. Forty-eight patients were randomized (25 to MVAC with rhGM-CSF and 23 to escalated MVAC alone). The clinical characteristics of the study populations were similar (ie, degree of tumor dissemination and performance status). RESULTS The dose-intensity in the two arms of the study did not differ significantly. No difference in the frequency of bacteriologically documented infections occurred between the two study arms. CONCLUSION The use of the hematopoietic growth factor rhGM-CSF did not result in an increased dose-intensity of escalated MVAC. The inability to increase the dose-intensity of MVAC further was a result of nonhematologic side effects of the chemotherapy. Escalation of treatment delivered at its median-tolerated dose is unlikely to result in additional therapeutic benefit for patients with common solid tumors. Future development of therapy may require the development of new agents or concepts, rather than modification of existing therapies.

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Goncharova, Valentina, Ingrid U. Schraufstaetter, Shinji Iizuka, Yu Yamaguchi y Sophia K. Khaldoyanidi. "Hyaluronan Expressed by Bone Marrow Mesenchymal Cells Regulates Functions of the Hematopoietic Microenvironment". Blood 120, n.º 21 (16 de noviembre de 2012): 1243. http://dx.doi.org/10.1182/blood.v120.21.1243.1243.

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Abstract Abstract 1243 While the quantity and quality of transplanted hematopoietic stem cells (HSC) are important for the recovery of hematopoiesis, the functional status of the regulatory hematopoietic microenvironment is a critical parameter that determines the regenerative function of HSCs. The quality of the microenvironment, i.e. its ability to support hematopoiesis, may be compromised under pathological circumstances such as during disease development or as a result of therapeutic interventions. Thus, the hematopoietic microenvironment should be allowed to recover prior to HSC transplantation. To effectively prepare the marrow microenvironment for HSC transplantation it is important to understand which of the molecular pathways regulating the function of the microenvironment are disrupted under the specific pathological condition. The involvement of hyaluronan (HA) in regulation of hematopoiesis has been previously suggested. However, whether HA contributes to the regulatory network of the hematopoietic microenvironment is not well understood. Since HA is highly susceptible to irradiation, which induces HA degradation and depolymerization leading to HA chain fragmentation and affecting its three-dimensional structure, sublethally irradiated mice (6Gy) were used to test the effect of exogenous HA on hematopoietic recovery. We found that administration of HA shortened the period of cytopenia compared to control mice which received vehicle only. To investigate whether the depletion of HA from the microenvironment has negative effects of hematopoietic homeostasis, knockout mice of three hyaluronan synthase genes (Has1, Has2, Has3) were generated as a mouse model of targeted HA deficiency in the hematopoietic microenvironment. Specifically, we generated double Has knockout (KO) mice (dHAS1/3 KO, Has1–/–;Has3–/–) and triple Has KO mice (tHAS1/2/3 KO, Prx1-Cre;Has2flox/flox;Has1–/–;Has3–/–). In the following study, wild type (WT), dHAS1/3 and tHAS1/2/3 KO mice were sublethally irradiated (6Gy) and the dynamics of hematopoietic recovery were tested. We found that the recovery of leukocytes in tHAS1/2/3 KO mice was significantly delayed as compared to WT and dHAS1/3 KO mice. This finding suggests that the HA-deficient microenvironment cannot support hematopoietic recovery following irradiation. Additional tests demonstrated that the number of hematopoietic progenitors was decreased in bone marrow and increased in extramedullary sites of tHAS1/2/3 KO mice as compared to WT and dHAS1/3/KO mice. In line with this observation, decreased hematopoietic activity was observed in long-term bone marrow cultures (LTBMC) from tHAS1/2/3 KO mice, whereas the formation of the adherent layer and generation of hematopoietic cells in WT and dHAS1/3/KO cultures was the same. 4-methylumbelliferone (4-MU) was used to pharmacologically inhibit the production of HA in LTBMC. Treatment with 4MU inhibited HA synthesis, decreased expression of HAS2 and HAS3 and eliminated hematopoiesis in LTBMC, and this effect was alleviated by the addition of exogenous HA. Exogenous HA also augmented the cell motility in LTBMC, which correlated with HA-stimulated production of chemokines and growth factors. Conditioned media from HA-induced LTBMC enhanced the chemotaxis of HSC in response to SDF-1. In addition, pharmacological inhibition of HA synthesis decreased homing of transplanted HSC into the marrow and interactions of HSC with endothelial cells under conditional physiological shear stress. Our findings demonstrate that HA depletion reduces the ability of the microenvironment to support HSPC, and confirm a role for HA as a necessary regulatory element in the structure of the hematopoietic microenvironment. Collectively, our results strongly suggest that HA is a biologically active component of the hematopoietic microenvironment and is involved in regulating hematopoietic homeostasis. Since some treatments or compounds reduce HA concentrations in tissues and some conditions are associated with increased levels of HA, it may prove clinically useful to monitor the dynamics of endogenous HA recovery to aid in identifying the optimal time for stem cell transplantation. Our data also suggest that biologically active exogenous HA polymers of the correct size, source, and conformation as well as HA synthesis inhibitors may have potential use in clinical hematology to correct misbalanced HA levels. Disclosures: No relevant conflicts of interest to declare.

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Kohrogi, Kensaku, Shinjiro Hino, Akihisa Sakamoto, Kotaro Anan, Ryuta Takase, Hirotaka Araki, Yuko Hino et al. "LSD1 defines erythroleukemia metabolism by controlling the lineage-specific transcription factors GATA1 and C/EBPα". Blood Advances 5, n.º 9 (30 de abril de 2021): 2305–18. http://dx.doi.org/10.1182/bloodadvances.2020003521.

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Abstract Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets. However, metabolic roles of LSD1 and lineage-dependent factors remain to be elucidated in AML cells. Here, we show that LSD1 directs a hematopoietic lineage-specific metabolic program in AML subtypes. Erythroid leukemia (EL) cells particularly showed activated glycolysis and high expression of LSD1 in both AML cell lines and clinical samples. Transcriptome, chromatin immunoprecipitation–sequencing, and metabolomic analyses revealed that LSD1 was essential not only for glycolysis but also for heme synthesis, the most characteristic metabolic pathway of erythroid origin. Notably, LSD1 stabilized the erythroid transcription factor GATA1, which directly enhanced the expression of glycolysis and heme synthesis genes. In contrast, LSD1 epigenetically downregulated the granulo-monocytic transcription factor C/EBPα. Thus, the use of LSD1 knockdown or chemical inhibitor dominated C/EBPα instead of GATA1 in EL cells, resulting in metabolic shifts and growth arrest. Furthermore, GATA1 suppressed the gene encoding C/EBPα that then acted as a repressor of GATA1 target genes. Collectively, we conclude that LSD1 shapes metabolic phenotypes in EL cells by balancing these lineage-specific transcription factors and that LSD1 inhibitors pharmacologically cause lineage-dependent metabolic remodeling.

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Basu, Sunanda y Hal E. Broxmeyer. "Role of Integrin Linked Kinase in Expansion and Chemotaxis of CD34+ Cord Blood Cells." Blood 114, n.º 22 (20 de noviembre de 2009): 3616. http://dx.doi.org/10.1182/blood.v114.22.3616.3616.

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Abstract 3616 Poster Board III-552 Despite being an excellent alternative to bone marrow or mobilized peripheral blood as a source of hematopoietic stem progenitor cells (HSPCs), the limiting factor to wider use of cord blood (CB) in transplantation is the 10-fold lower cell dose in a typical CB unit compared to harvested bone marrow or peripheral blood stem cells. Successful ex-vivo expansion of HSPCs as well as increasing transplantation efficiency by adopting protocols that enhance homing and engraftment of transplanted HSPC provides hope of making the applicability of a single unit of CB wider in the adult population. Interaction and adhesion of HSPCs with extracellular matrix (ECM) is an important event that regulates cell differentiation, proliferation, survival/ apoptosis as well as migration of HSPCs. Based on evidence present in the literature it appears that in addition to cooperative action between adhesion and growth factors, integrin mediated cell adhesion also provides distinct growth regulatory cues. Although it is known that in hematopoietic system, β1 integrin plays an important role in the interaction of HSPCs with integrin ligands, the underlying molecular mechanisms regulating βl integrin activity in hematopoietic cells remains largely unknown. Based on studies in other systems- Integrin linked kinase (ILK) appears to be an important molecule. ILK not only modulates β1 integrin activity, but also functions as an adapter protein, physically coupling downstream signals from both integrins and growth factors. ILK is preferentially expressed in murine stem / early progenitor cells (based on I. Lemiscka's Stem cell database) and we have found that ILK is expressed in both primitive (CD38-/loCD34+) and committed progenitor (CD38+ CD34+) cells from CB by western blot. Moreover, using a co-immunoprecipitation approach, we found that in freshly isolated CD34+CB cells ILK interacts with β1 integrin. To investigate the role of ILK in adhesion-dependent and -independent growth of CB CD34+ cells both in the presence and absence of growth factors we expressed constitutive active ILK (CAILK) or dominant negative ILK (DNILK) in CD34+CB cells. In addition, we have also evaluated the effect of modulating ILK activity on chemotaxis of CD34+ CB cells towards stromal derived factor-1 (SDF-1)/CXCL12. We found that expression of CAILK enhances expansion of total CD34+ cells as well as colony forming cells stimulated ex-vivo by growth factors (stem cell factor- SCF; Flt-3 ligand and thrombopoietin-TPO), compared to cells transfected with vector alone. In contrast, expression of DNILK inhibited expansion of CD34+CB cells; this effect was more pronounced when cells were cultured in the absence of fibronectin, the ECM. Expression of CAILK increases cell-cycling since a greater proportion of cells were in ‘S’-phase compared to cells expressing DNILK or vector alone, both when the cells were expanded in the presence or absence of fibronectin for 20h. Expression of CAILK also leads to improved survival of CD34+ cells in the absence of serum and growth factors. Interestingly, β-catenin could be detected in CD34+ cells expressing CAILK, but not in cells transfected with DNILK or vector alone. Furthermore, in response to growth factor stimulation, Akt is phosphorylated in cells expressing either CAILK or DNILK; however, the amount of Akt phosphorylation was lower in cells expressing DNILK. Expression of CAILK improved modestly but not significantly the chemotaxis of CD34+ cells towards SDF-1 compared to cells expressing vector alone. However, DNILK significantly impaired chemotaxis of CD34+CB cells towards SDF-1. This impairment of chemotaxis is associated with defective actin polymerization in response to SDF-1, both at the ‘leading-edge’ and ‘tail’ of a polarized DNILK expressing CD34+ cell. Our findings implicate a role for ILK in both growth factor stimulated ex-vivo expansion of HSPCs as well as SDF-1 mediated chemotaxis. This may have potential implications in the therapeutic use of CB cells. Disclosures: No relevant conflicts of interest to declare.

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Pleimes, Dirk, Vivienne Bunker, Michael Meyer y Maciej Czajkowski. "Effects of a Novel Orally Bioavailable Small Molecule (Imidazolyl Ethanamide Pentandioic Acid) on Acute Radiation Syndrome". Blood 132, Supplement 1 (29 de noviembre de 2018): 5089. http://dx.doi.org/10.1182/blood-2018-99-114490.

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Abstract Introduction Acute radiation syndrome (ARS) develops within 24 hours of exposure to ionizing radiation. Leukocyte growth factors have been used to reduce mortality and mitigate the hematopoietic symptoms of ARS. Three subcutaneously applied radiomitigators G-CSF, Peg-G-CSF and GM-CSF have been approved by the FDA as medical countermeasures but few others are under development. Imidazolyl ethanamide pentandioic acid (IEPA, Myelo001) is a novel small molecule for the treatment of ARS. Preclinical and clinical studies have shown that IEPA applied orally or intraperitoneally was effective in reducing hematopoietic symptoms caused by radiation and chemotherapy. Objective To investigate the effects of IEPA as a radioprotector (prophylactic) and radiomitigator (therapeutic) for ARS and hematopoietic syndrome of ARS (H-ARS). Methods Multiple oral or intraperitoneal administrations of IEPA (25 or 50 mg/kg doses) and radiation levels of 5.8 Gy (estimated LD25/30) and 6.0 Gy (estimated LD50/30) on mortality, body weight and bone marrow cellularity were assessed in a mouse model. 205 C57BL/6 mice were subdivided into 1 unirradiated group, 6 groups exposed to 5.8 Gy, and 2 groups exposed to 6.0 Gy. Prophylactic treatment (25 or 50 mg/kg) was started 3 days before total-body irradiation, while therapeutic treatment (50 mg/kg) was begun 24 h post exposure. The 6 LD25/30 groups consisted of a vehicle control group (VL; 2), twice daily intraperitoneally administered IEPA (ML; 3), orally twice a day (ML; 4) or once a day (ML; 5), G-CSF positive control subcutaneously administered once a day (GL; 6) or in combination with IEPA (M/GL; 7). The 2 LD50/30 groups consisted of a vehicle control group (VH; 8) and a group administered IEPA orally once a day (MH; 9). The experiments assessed mortality using Kaplan-Meier estimator, body weight and bone marrow cellularity over the course of 30 days with prescheduled sacrifices of subgroups on days 7, 14 and 30. Results No significant benefit of prophylactic and therapeutic treatment on survival in the lower (5.8 Gy) irradiation group was detected. Groups ML; 3 and ML; 4 had a dose reduction factor (DFR) < 1 vs VL; 2 whereas ML; 5, GL; 6 and M/GL; 7 had a DRFs > 1. In the high radiation group (6.0 Gy), the Kaplan-Meier estimator revealed an increase in survival (85 %) after therapy compared to controls (56 %). The dose reduction factor in group MH; 9 compared to the controls (VH; 8) was 1.5. The highest protective effect on body weight was observed in the therapeutic regimen (MH; 9) used for 6.0 Gy exposure, which showed a positive effect on days 15, 21 and 30. Therapeutic IEPA treatment mitigated the impact of radiation on bone marrow cellularity. A pronounced effect on peripheral hematology was neither observed in the prophylactic, therapeutic IEPA nor the positive control G-CSF treated groups. Conclusions Different routes of administration and doses of IEPA in the prophylactic groups did not alter ARS symptoms. However, therapeutic treatment in the LD25/30 setting with IEPA and G-CSF, and the LD50/30 setting with IEPA at a dose of 50 mg/kg showed a reduction in mortality and weight loss compared to the controls. Additionally, IEPA treatment mitigated the impact of radiation on bone marrow cellularity. Analysis of peripheral blood did not reveal significant differences across the treatment groups probably due to no optimal time point analysis. Limitations included the small size of the prophylactically treated groups exposed to a low radiation dose. Disclosures Pleimes: Bayer: Consultancy, Equity Ownership; Myelo Therapeutics: Employment, Equity Ownership. Bunker:Myelo Therapeutics: Other: Contract Research via SNBL USA on behalf and in account of Myelo Therapeutics GmbH; SNBL USA: Employment. Meyer:Myelo Therapeutics GmbH: Consultancy. Czajkowski:Myelo Therapeutics GmbH: Employment.

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Kalra, R., D. Dale, M. Freedman, MA Bonilla, M. Weinblatt, A. Ganser, P. Bowman, S. Abish, J. Priest y RS Oseas. "Monosomy 7 and activating RAS mutations accompany malignant transformation in patients with congenital neutropenia". Blood 86, n.º 12 (15 de diciembre de 1995): 4579–86. http://dx.doi.org/10.1182/blood.v86.12.4579.bloodjournal86124579.

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Individuals with severe forms of congenital neutropenia suffer from recurrent infections. The therapeutic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to increase the neutrophil count is associated with fewer infections and an improved quality of life. However, the long-term effects of this new therapy are largely unknown. In particular, it is unclear if myeloid leukemia, a known complication of some forms of congenital neutropenia, will occur with increased frequency among patients who receive long-term treatment with hematopoietic growth factors. We report 13 patients with congenital disorders of myelopoiesis who developed leukemic transformation with either myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) and 1 who acquired a clonal cytogenetic abnormality without evidence of MDS or AML while receiving rhG-CSF. The bone marrows of 10 patients showed monosomy 7 and 5 had activating RAS mutations. These abnormalities were not detected in pretreatment bone marrows and cessation of rhG-CSF was not associated with either clinical improvement or cytogenetic remission. We conclude that patients with severe forms of congenital neutropenia are at relatively high risk of developing MDS and AML. The occurrence of monosomy 7 and RAS mutations in these cases suggests that the myeloid progenitors of some patients are genetically predisposed to malignant transformation. The relationship between therapeutic rhG-CSF and leukemogenesis in patients with severe chronic neutropenia is unclear.

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Tabayashi, Takayuki, Yasuyuki Takahashi, Yuta Kimura, Tatsuki Tomikawa, Morihiko Sagawa, Tomoe Nemoto, Reiko Watanabe, Michihide Tokuhira, Shigehisa Mori y Masahiro Kizaki. "Targeting the Wnt/β-Catenin Signaling Pathway in Multiple Myeloma: A Possible New Therapeutic Approach to Overcome Bortezomib-Resistance". Blood 124, n.º 21 (6 de diciembre de 2014): 3372. http://dx.doi.org/10.1182/blood.v124.21.3372.3372.

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Abstract Multiple myeloma (MM) is a neoplasm of plasma cells that is often fatal, despite the use of high dose chemotherapy and hematopoietic stem cell transplantation. Although new therapeutic approaches, including novel agents such as thalidomide, lenalidomide, and bortezomib (a proteasome inhibitor), are now used clinically and have improved the outcome of patients with MM, most patients eventually relapse, and it remains an incurable disease. Wnt/β-catenin signaling plays a critical role in both cell proliferation and differentiation in normal tissue. β-catenin, a key player and downstream effector in canonical Wnt signaling, is involved in the regulation of cell fate, proliferation, and self renewal of stem cells. The activation of Wnt signaling is aberrantduring the pathogenesis of various malignant neoplasms, and it has been suggested that Wnt/β-catenin signaling is involved in the regulation of cancer stem cells. When the Wnt signaling pathway is activated, stabilized β-catenin translocates to the nucleus, where it interacts with T-cell factor, followed by transcription of target genes such as c-myc, cyclin D1 and survivin. Nuclear β-catenin also recruits the co-activator, cyclic AMP response element-binding protein (CBP), which is essential for hematopoietic cell proliferation and hematopoietic stem cell self renewal, or its related homolog p300, which is involved in hematopoietic cell differentiation. Recent studies have shown that CBP and p300 have distinct functions in the regulation of β-catenin expression: CBP promotes β-catenin expression, whereas p300 inhibits β-catenin expression. In the context of hematological malignancies, β-catenin is overexpressed in myeloma-derived cell lines and primary myeloma cells, whereas expression is very low in normal plasma cells. Myeloma cells are maintained by several growth factors and cytokines, including Wnt ligands secreted by stromal cells in the bone marrow. These data suggest that Wnt/β-catenin signaling contributes to the pathogenesis of MM and thus might be a promising target for the treatment of this incurable hematological malignancy. Moreover, it has been reported that CBP, rather than p300, plays an important role in the expression of apurinic endonuclease/redox factor-1, an important regulator of multidrug resistance, in retinoic acid-induced chemo-resistant myeloma cells, suggesting that CBP is involved in the acquisition of drug resistance. Taken together with the previous data, Wnt/β-catenin signaling, especially CBP, might be an attractive target for new therapeutic agents against MM. ICG-001, small-molecule inhibitor of the canonical Wnt signaling pathway, specifically binds to CBP, thereby disrupting CBP/β-catenin interaction. In the present study, we investigated the role of Wnt/β-catenin signaling in myeloma cells using ICG-001. MTS and trypan blue dye exclusion assays showed that ICG-001 inhibits the proliferation of U266, RPMI8226, and KMS myeloma cell lines in a dose- (0-15 μM) and time- (0-72 h) dependent manner. Assays for apoptotic cell death were performed to determine the cause of growth inhibition by ICG-001 and demonstrated that ICG-001 induced both early and late apoptosis in myeloma cells. To investigate the molecular mechanisms of ICG-001-induced cell death in myeloma cells, the expression of various cell-death associated proteins and down-stream molecules of Wnt/β-catenin signaling was examined. Western blotting analysis showed that ICG-001 arrested cell growth and induced apoptotic cell death in myeloma cells by reducing the expression of three β-catenin target molecules: survivin, cyclin D1, and c-Myc. We next examined the effects of ICG-001 on bortezomib (BTZ)-resistant MM cells. BTZ resistance is an urgent issue in clinics, and therapeutic approaches for overcoming BTZ resistance are important. Interestingly, ICG-001 inhibited the proliferation of both BTZ-sensitive wild-type KMS and BTZ-resistant KMS cells, suggesting that targeting CBP may overcome BTZ-resistance. Furthermore, when combined with cyclosporine, which inhibits non-canonical Wnt/β-catenin signaling, ICG-001 synergistically induced the growth arrest of myeloma cells by inducing apoptotic cell death. These results indicate that inhibition of Wnt/β-catenin signaling may be an attractive therapeutic option both for patients with newly diagnosed MM and for those in a refractory or relapsed state. Disclosures No relevant conflicts of interest to declare.

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Singh, Pratibha, Seiji Fukuda, Mary R. Saunders y Louis M. Pelus. "Survivin Is a Master Regulator of Mesenchymal Stem Cell Functions and Potential Therapeutic Target for Mesenchymal Stem Cell Expansion". Blood 124, n.º 21 (6 de diciembre de 2014): 774. http://dx.doi.org/10.1182/blood.v124.21.774.774.

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Mesenchymal stemcells (MSCs) are found throughout adult organisms and are involved in tissue maintenance and repair, as well as in the regulation of hematopoiesis and immunologic responses. Several clinical trials are currently under way to use allogeneic MSCs for enhancement of hematopoietic stem cell transplantation and treatment of graft-versus-host disease, spinal cord injury, cartilage and meniscus repair, and stroke. However, the therapeutic uses of MSCs can be limited by insufficient MSC number, their survival, and their ability to differentiate into multiple lineages, pointing to an important need to identify factors regulating MSC survival, proliferation, and differentiation. In this study, we explored the role of the anti-apototic protein Survivin in MSC functions. Survivin is an intracellular member of the inhibitor-of-apoptosis protein (IAP) family and is implicated in regulation of apoptosis, cell division, and cell cycle control of many cell types including hematopoietic stem cells, leukemic cells, and endothelial cells. However, whether Survivin is involved in MSC activity or function is unknown. Using flow cytometry and function assays, we found that adult mouse and human MSCs, identified as CD45-Ter119-CD51+PDGFR+Nestin+ cells, express high levels of Survivin, which regulates MSCs survival and expansion under normal physiological and stressful conditions. Flow cytometry analysis revealed that approximately 40.5±3.6% of mouse bone marrow MSCs, 33.6±4.2% of adult human bone marrow MSCs, and 43.6±5.3% human cord blood MSCs express Survivin. Treatment of mice in vivo with YM155 (10 mg/kg), a small molecule Survivin inhibitor, for 6 days decreased bone marrow CD45-Ter119-CD51+PDGFR+Nestin+ MSC by 2.1 fold and functional fibroblast colony formation (CFU-F) by 2.8 fold. Survivin gene deletion using Survivin-specific SiRNA decreased mouse and human bone marrow derived MSCs number and CFU-F ability by 3.2 fold and 2.8 fold respectively. Retroviral overexpression of Survivin in mouse MSCs enhanced CFU-F formation by 4 fold. In an in vitro wound healing assay YM155-treated MSCs recovered more slowly compared to control cultures. To determine underlying mechanisms involved in Survivin dependent regulation of MSC function, we measured the survival and proliferation of YM155 treated MSCs. Treatment of mouse or human bone marrow-derived MSCs with YM155 (50 nmol/l) for 48 hours enhanced the caspase 3 and 7 expression by 42.8% and 63.9% respectively, while BrdU incorporation was similar in control and YM155-treated MSCs, suggesting that Survivin is primarily involved in MSC survival. To explore whether Survivin is also involved in growth factor-mediated MSC survival and expansion, mouse bone marrow derived MSCs were cultured in the presence of platelet derived growth factor (PDGF) or basic fibroblast growth factor (b-FGF) with or without the Survivin inhibitor YM155. PDGF enhanced the Survivin expression by 52.8±2.2% and b-FGF enhanced Survivin expression by 43.8±4.5% and increased the CFU-F counts by 5.6 fold and 4.2 fold, respectively. In contrast, YM155 treated MSCs did not show any enhancement in Survivin expression, and CFU-F were substantially lower than the corresponding controls (PDGF or b-FGF treated cultures). To determine whether Survivin affects the Survival of stressed MSCs, we exposed mouse bone marrow MSCs to 4 Gy irradiation dose and followed by culture for 3 days with or without the Survivin inhibitor YM155. Irradiation alone reduced the survival of MSCs by 53.5%, however the viability of irradiated MSCs treated with YM155 was reduced by 82.8%. The hallmark of MSC function is the capacity to differentiate into several mesodermal lineages. We found that the exposure of MSC cultures to YM155 during the lineage differentiation process inhibits MSC osteogenic and adipogenic differentiation while sparing chondrogenic cell differentiation. In conclusion, our study demonstrates that Survivin controls basal and growth factor dependent survival and expansion of mouse and human MSCs, and protects them from irradiation induced cell death. Furthermore, our data suggest the regulating Survivin expression in MSCs would be beneficial to enhance MSC recovery for clinical utility. Disclosures No relevant conflicts of interest to declare.

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Löwenberg, B., M. A. Boogaerts, S. M. Daenen, G. E. Verhoef, A. Hagenbeek, E. Vellenga, G. J. Ossenkoppele et al. "Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia." Journal of Clinical Oncology 15, n.º 12 (diciembre de 1997): 3496–506. http://dx.doi.org/10.1200/jco.1997.15.12.3496.

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PURPOSE The hematopoietic growth factors (HGFs) introduced into induction chemotherapy (CT) of acute myeloid leukemia (AML) might be of benefit to treatment outcome by at least two mechanisms. HGFs given on days simultaneously with CT might sensitize the leukemic cells and enhance their susceptibility to CT. HGFs applied after CT might hasten hematopoietic recovery and reduce morbidity or mortality. MATERIALS AND METHODS We set out to evaluate the use of granulocyte-macrophage colony-stimulating factor (GM-CSF; 5 microg/kg) in a prospective randomized study of factorial design (yes or no GM-CSF during CT, and yes or no GM-CSF after CT) in patients aged 15 to 60 years (mean, 42) with newly diagnosed AML. GM-CSF was applied as follows: during CT only (+/-, n = 64 assessable patients), GM-CSF during and following CT (+/+, n = 66), no GM-CSF (-/-, n = 63), or GM-CSF after CT only (-/+, n = 60). RESULTS The complete response (CR) rate was 77%. At a median follow-up time of 42 months, probabilities of overall survival (OS) and disease-free survival (DFS) at 3 years were 38% and 37% in all patients. CR rates, OS, and DFS did not differ between the treatment groups (intention-to-treat analysis). Neutrophil recovery (1.0 x 10(9)/L) and monocyte recovery were significantly faster in patients who received GM-CSF after CT (26 days v 30 days; neutrophils, P < .001; monocytes, P < .005). Platelet regeneration, transfusion requirements, use of antibiotics, frequency of infections, and duration of hospitalization did not vary as a function of any of the therapeutic GM-CSF modalities. More frequent side effects (eg, fever and fluid retention) were noted in GM-CSF-treated patients predominantly related to the use of GM-CSF during CT. CONCLUSION Priming of AML cells to the cytotoxic effects of CT by the use of GM-CSF during CT or accelerating myeloid recovery by the use of GM-CSF after CT does not significantly improve treatment outcome of young and middle-aged adults with newly diagnosed AML.

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Nowak, Witold N., Hevidar Taha, Joanna Markiewicz, Neli Kachamakova-Trojanowska, Jacek Stępniewski, Damian Klóska, Urszula Florczyk-Soluch et al. "Atorvastatin and Conditioned Media from Atorvastatin-Treated Human Hematopoietic Stem/Progenitor-Derived Cells Show Proangiogenic Activity In Vitro but Not In Vivo". Mediators of Inflammation 2019 (16 de julio de 2019): 1–15. http://dx.doi.org/10.1155/2019/1868170.

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Myeloid angiogenic cells (MAC) derive from hematopoietic stem/progenitor cells (HSPCs) that are mobilized from the bone marrow. They home to sites of neovascularization and contribute to angiogenesis by production of paracrine factors. The number and function of proangiogenic cells are impaired in patients with diabetes or cardiovascular diseases. Both conditions can be accompanied by decreased levels of heme oxygenase-1 (HMOX1), cytoprotective, heme-degrading enzyme. Our study is aimed at investigating whether precursors of myeloid angiogenic cells (PACs) treated with known pharmaceuticals would produce media with better proangiogenic activity in vitro and if such media can be used to stimulate blood vessel growth in vivo. We used G-CSF-mobilized CD34+ HSPCs, FACS-sorted from healthy donor peripheral blood mononuclear cells (PBMCs). Sorted cells were predominantly CD133+. CD34+ cells after six days in culture were stimulated with atorvastatin (AT), acetylsalicylic acid (ASA), sulforaphane (SR), resveratrol (RV), or metformin (Met) for 48 h. Conditioned media from such cells were then used to stimulate human aortic endothelial cells (HAoECs) to enhance tube-like structure formation in a Matrigel assay. The only stimulant that enhanced PAC paracrine angiogenic activity was atorvastatin, which also had ability to stabilize endothelial tubes in vitro. On the other hand, the only one that induced heme oxygenase-1 expression was sulforaphane, a known activator of a HMOX1 inducer—NRF2. None of the stimulants changed significantly the levels of 30 cytokines and growth factors tested with the multiplex test. Then, we used atorvastatin-stimulated cells or conditioned media from them in the Matrigel plug in vivo angiogenic assay. Neither AT alone in control media nor conditioned media nor AT-stimulated cells affected numbers of endothelial cells in the plug or plug’s vascularization. Concluding, high concentrations of atorvastatin stabilize tubes and enhance the paracrine angiogenic activity of human PAC cells in vitro. However, the effect was not observed in vivo. Therefore, the use of conditioned media from atorvastatin-treated PAC is not a promising therapeutic strategy to enhance angiogenesis.

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Majka, Marcin, Magdalena Kucia y Mariusz Z. Ratajczak. "Stem cell biology: a never ending quest for understanding." Acta Biochimica Polonica 52, n.º 2 (25 de junio de 2005): 353–58. http://dx.doi.org/10.18388/abp.2005_3448.

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Stem cells (SC) research is an important part of biotechnology that could lead to the development of new therapeutic strategies. A lot of effort has been put to understand biology of the stem cells and to find genes and subsequently proteins that are responsible for their proliferation, self-renewal and differentiation. Different cytokines and growth factors has been used to expand stem cells, but no combination of these factors was identified that could effectively expand the most primitive stem cells. Recently, however, genes and receptors responsible for SC proliferation and differentiation have been described. Ligands for these receptors or these genes themselves are being already used for ex vivo expansion of stem cells and the first data are very promising. New markers, such as CXCR4 and CD133, have been discovered and shown to be present on surface of hematopoietic stem cells. The same markers were recently also found to be expressed on neuronal-, hepatic- or skeletal muscle-stem cells. By employing these markers several laboratories are trying to isolate stem cells for potential clinical use. New characteristics of stem cells such as transdifferentiation and cell fusion have been described. Our team has identified a population of tissue committed stem cells (TCSC). These cells are present in a bone marrow and in other tissues and they can differentiate into several cell types including cardiac, neural and liver cells.

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28

Bashirov, Farid V., Ilnur I. Salafutdinov, Michail E. Sokolov, Andrew A. Izmailov, Vage A. Markosyan, Filip O. Fadeev, Albert Rizvanov y Rustem I. Islamov. "Umbilical Cord Blood Mononuclear Cells for Ex-Vivo Gene Therapy". Blood 132, Supplement 1 (29 de noviembre de 2018): 5797. http://dx.doi.org/10.1182/blood-2018-99-113462.

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Abstract Cell-mediated (ex-vivo) gene therapy for the treatment of adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) had started in 1990 and nowadays it is the first marketing approval of an ex vivo gene therapy in Europe. The method based on ex-vivo transduction of peripheral blood lymphocytes with retroviral vector carrying the functional ADA gene in 2002 have been improved to use hematopoietic stem cell (HSC) for ex-vivo transduction with 100% survival and the evidence of safety and efficacy. Remarkably, umbilical cord blood mononuclear cells (UCB-MC) were successfully used for treatment of ADA deficiency in neonates as well. Meanwhile SCID is a very rare congenital disorder of the immune system although the option to use peripheral blood lymphocytes as cell carriers of the therapeutic genes for regenerative medicine is highly attractive. In our studies to overcome the neural cells death and stimulate neuroregeneration at neurodegenerative diseases (ALS), spinal cord injury (SCI), and stroke in animal models we employed ex-vivo triple gene therapy based on human UCB-MC transduced with adenoviral vectors carrying vascular endothelial growth factor (VEGF), glial cell-derived neurotrophic factor (GDNF) and neural cell adhesion molecule (NCAM). The reason for clinical application of UCB-MC is based on their availability, ease of preparation and potential for long term storage, as well as legislative, ethical and religious benefits for the transplantation. In our gene-cell construct NCAM was used for homing and survival of UCB-MC at the site of neurodegeneration. VEGF and GDNF are the molecules with well-known neuroprotective function. Moreover VEGF is useful in restoring of the microcirculation as well. The positive results in treatment of ALS mice (Islamov et al, 2016), SCI (Izmailov et al, 2017) and stroke in rats (Sokolov et al, 2018) let us to propose the rationality to use of UCB-MC as cell carriers for the therapeutic genes based on:(1) suitability for both auto- and allotransplantation; (2) low immunogenicity; (3) high level of transduction; (4) high capability of synthetic and secretory activity for production of recombinant therapeutic molecules as well as endogenous growth and neurotrophic factors, cytokines and chemokines; (5) the action of therapeutic molecules on target cells via the paracrine or endocrine mechanism; (6) duration of recombinant molecule production limited by adenoviral vector half-life; (7) elimination of UCB-MC in 1-2 month after administration and possible multiple transplantation. Important, cell-mediated gene delivery makes the viral antigens inside the ex-vivo transduced UCB-MC invisible to the recipient immune system and it is easy to control production of recombinant molecules via the level of cell transduction or the number of transplanted cells. Thus, the cord blood mononuclear cells can serve as powerful tools for address delivery of recombinant genes encoding therapeutic molecules for regenerative medicine. This study was supported by the grant of Russian Science Foundation No 16-15-00010. Kazan Federal University was supported by the Russian Government Program of Competitive Growth. Disclosures No relevant conflicts of interest to declare.

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29

Dighe, Niraja, Subhashree Venkatesan, Poon Zhiyong y William YK Hwang. "Mechanism of Action of Azacytidine in Myelodysplastic Syndromes (MDS)". Blood 128, n.º 22 (2 de diciembre de 2016): 4315. http://dx.doi.org/10.1182/blood.v128.22.4315.4315.

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Abstract Introduction: Myelodysplastic syndromes (MDS) have historically been classified as a set of heterogeneous hematopoietic stem cell (HSC) disorders, which are characterized clinically by abnormalities in the hematopoietic system. However, several recent landmark studies have now demonstrated that the pathogenesis of MDS is not confined to HSCs, and mesenchymal stromal cells (MSCs) in the bone marrow also play important contributing roles in sustaining the disorder. Treatment for MDS using hypomethylating agents such as azacytidine is effective, with patients showing recovery of blood counts and long-term restoration of normal hematopoiesis - an outcome that is plausibly brought about only by the reversal of abnormalities the bone marrow stem cell niches. In this work, we investigate the use of azacytidine in both HSCs and MSCs of MDS patients in order to better understand its therapeutic mechanism on stem cell niches, as well as to inform strategies for the development of future therapies for similar hematopoietic disorders. Methods: Cryopreserved BM MDS samples (n=20) were obtained from the Department of Hematology repository at Singapore General Hospital. Healthy MSCs were derived from bone marrow aspirates of healthy donors, obtained at Singapore General Hospital. Healthy CD34+ HSCs were purchased from Lonza. Osteogeneic and adipogeneic differentiation capabilities and proliferation capacities were performed on MSCs. Proliferation, cell cycling and apoptosis in HSCs were analysed. Gene expression profiling for MDS candidate genes was performed by quantitative PCR on both MSCs and HSCs. Co-culture experiments with healthy CD34+ cells on MDS MSCs were investigated. All assays were performed on both MSCs and HSCs, before and after azacytidine treatment. Results: MDS MSCs have significantly reduced proliferative capacities (p=0.02) and osteogeneic differentiation potentials (p=0.0006) compared to healthy MSCs. Gene expression profiling of MDS MSCs showed a 4.6-fold (n=17; p=0.0002) and 6.2-fold (n=15; p=0.0002) reduction in osteogeneic markers like Runx2 and Osterix respectively. Hematopoietic growth factors and chemokines such as IGF1, IL-8 and Angiopoietin-1 are 5.35-fold (n=17; p<0.0001), 3.36-fold (n=20; p=0.02) and 1.45-fold (n=15; p=0.2) lower than healthy controls. After treatment with azacytidine, MDS MSCs demonstrated significant increased proliferative capacities (n=4; p<0.0001) and differentiation potentials (n=3; p<0.0001) in comparison to healthy MSCs. Significant increase in gene expression of Osterix (n=5; p<0.0001) was seen in comparison to healthy controls. In MDS HSCs, expression of hematopoietic, cell cycling and apoptosis genes such as CXCR4, CCL3, Cyclin D1 and BCL2 are significantly different from healthy HSC - 13 fold (n=15; p=0.1005), 6.8 fold (n=15; p=0.014), 20 fold (n=19; p=0.2673) and 5.26 fold (n=19; p=0.0478) lower than healthy HSCs, respectively. Proliferation of MDS HSCs in culture was 3.3 fold higher than healthy HSCs but treatment with azacytidine of 1µM and 5µM reduced the growth advantage of MDS HSCs to 3 fold and 4.2 fold in comparison with similarly treated healthy controls. Co-culture experiments of healthy CD34+ cells on MDS MSCs, induced a gene expression profile in healthy HSCs similar to MDS HSC. After treatment of MDS MSCs with azacytidine, the gene expression of expanded healthy CD34+ cells was normal. Conclusion: MDS stromal cells are functionally abnormal and have the ability to instruct healthy HSCs to adopt genetic features that resemble MDS HSCs. Treatment with azacytidine restores normal function to MDS MSCs while conferring a growth disadvantage to MDS HSCs but not healthy HSCs. These observations help elucidate for the first time a possible mechanism of action by azacytidine on stromal cells in the treatment of MDS and further suggest that therapies which also target stromal elements in bone marrow niches may be necessary in achieving more favorable outcomes for hematopoieic disorders such as MDS. Disclosures Hwang: Janssen-Cilag, Singapore: Honoraria, Other: Travel Support; Celgene, Singapore: Honoraria, Other: Travel Support; Roche, Singapore: Honoraria, Other: Travel Support; Pfizer, Singapore: Honoraria, Other: Travel Support; Novartis, Singapore: Honoraria, Other: Travel Support; BMS, Singapore: Honoraria, Other: Travel Support; MSD, Singapore: Honoraria, Other: Travel Support; Sanofi, Singapore: Honoraria, Other: Travel Support.

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30

Kruger, Ryan G., Helai Mohammad, Kimberly Smitheman, Monica Cusan, Yan Liu, Melissa Pappalardi, Kelly Federowicz et al. "Inhibition Of LSD1 As a Therapeutic Strategy For The Treatment Of Acute Myeloid Leukemia". Blood 122, n.º 21 (15 de noviembre de 2013): 3964. http://dx.doi.org/10.1182/blood.v122.21.3964.3964.

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Abstract Lysine specific demethylase 1 (LSD1) is a histone H3K4me1/2 demethylase found in various transcriptional co-repressor complexes. These complexes include Histone Deacetylases (HDAC1/2) and Co-Repressor for Element-1-Silencing Transcription factor (CoREST). LSD1 mediated H3K4 demethylation can result in a repressive chromatin environment that silences gene expression. LSD1 has been shown to play a role in development in various contexts. LSD1 can interact with pluripotency factors in human embryonic stem cells and is important for decommissioning enhancers in stem cell differentiation. Beyond embryonic settings, LSD1 is also critical for hematopoietic differentiation. LSD1 is overexpressed in multiple cancer types and recent studies suggest inhibition of LSD1 reactivates the all-trans retinoic acid receptor pathway in acute myeloid leukemia (AML). These studies implicate LSD1 as a key regulator of the epigenome that modulates gene expression through post-translational modification of histones and through its presence in transcriptional complexes. The current study describes the anti-tumor effects of a novel LSD1 inhibitor (GSK2879552) in AML. GSK2879552 is a potent, selective, mechanism-based, irreversible inhibitor of LSD1. Screening of over 150 cancer cell lines revealed that AML cells have a unique requirement for LSD1. While LSD1 inhibition did not affect the global levels of H3K4me1 or H3K4me2, local changes in these histone marks were observed near transcriptional start sites of putative LSD1 target genes. This increase in the transcriptionally activating histone modification correlated with a dose dependent increase in gene expression. Treatment with GSK2879552 promoted the expression of cell surface markers, including CD11b and CD86, associated with a differentiated immunophenotype in 12 of 13 AML cell lines. For example, in SKM-1 cells, increases in cell surface expression of CD86 and CD11b occurred after as early as one day of treatment with EC50 values of 13 and 7 nM respectively. In a separate study using an MV-4-11 engraftment model, increases in CD86 and CD11b were observed as early as 8 hours post dosing. GSK2879552 treatment resulted in a potent anti-proliferative growth effect in 19 of 25 AML cell lines (average EC50 = 38 nM), representing a range of AML subtypes. Potent growth inhibition was also observed on AML blast colony forming ability in 4 out of 5 bone marrow samples derived from primary AML patient samples (average EC50 = 205 nM). The effects of LSD1 inhibition were further characterized in an in vivo mouse model of AML induced by transduction of mouse hematopoietic progenitor cells with a retrovirus encoding MLL-AF9 and GFP. Primary AML cells were transplanted into a cohort of secondary recipient mice and upon engraftment, the mice were treated for 17 days. After 17 days of treatment, control treated mice had 80% GFP+ cells in the bone marrow whereas treated mice possessed 2.8% GFP positive cells (p<0.012). The percentage of GFP+ cells continued to decrease to 1.8% by 1-week post therapy. Remarkably, in a preliminary assessment for survival, control-treated mice succumbed to AML by 28 days post transplant, while treated mice showed prolonged survival. Together, these data demonstrate that pharmacological inhibition of LSD1 may provide a promising treatment for AML by promoting differentiation and subsequent growth inhibition of AML blasts. GSK2879552 is currently in late preclinical development and clinical trials are anticipated to start in 2014. All studies were conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and were reviewed the Institutional Animal Care and Use Committee either at GSK or by the ethical review process at the institution where the work was performed. Disclosures: Kruger: GlaxoSmithKline Pharmaceuticals: Employment. Mohammad:GlaxoSmithKline Pharmaceuticals: Employment. Smitheman:GlaxoSmithKline Pharmaceuticals: Employment. Liu:GlaxoSmithKline Pharmaceuticals: Employment. Pappalardi:GlaxoSmithKline Pharmaceuticals: Employment. Federowicz:GlaxoSmithKline Pharmaceuticals: Employment. Van Aller:GlaxoSmithKline Pharmaceuticals: Employment. Kasparec:GlaxoSmithKline Pharmaceuticals: Employment. Tian:GlaxoSmithKline Pharmaceuticals: Employment. Suarez:GlaxoSmithKline Pharmaceuticals: Employment. Rouse:GlaxoSmithKline Pharmaceuticals: Employment. Schneck:GlaxoSmithKline Pharmaceuticals: Employment. Carson:GlaxoSmithKline Pharmaceuticals: Employment. McDevitt:GlaxoSmithKline Pharmaceuticals: Employment. Ho:GlaxoSmithKline Pharmaceuticals: Employment. McHugh:GlaxoSmithKline Pharmaceuticals: Employment. Miller:GlaxoSmithKline Pharmaceuticals: Employment. Johnson:GlaxoSmithKline Pharmaceuticals: Employment. Armstrong:Epizyme Inc.: Has consulted for Epizyme Inc. Other. Tummino:GlaxoSmithKline Pharmaceuticals: Employment.

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31

Thompson, Zanshe, Melanie Rodriguez, Georgina Anderson, Seth Gabriel, Vera Binder, Leonard I. Zon y Katie L. Kathrein. "Ing4 Suppresses Quiescence and Inflammation in Hematopoietic Stem Cells". Blood 136, Supplement 1 (5 de noviembre de 2020): 16. http://dx.doi.org/10.1182/blood-2020-143388.

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Hematopoietic stem and progenitor cell (HSPC) development and maintenance is regulated through a complex regulatory network. In a screen of epigenetic regulators of hematopoiesis in zebrafish, we identified a requirement for the tumor suppressor protein, Inhibitor of growth 4 (Ing4) in HSPC specification. Ing4 acts to regulate transcription through interactions with transcription factors, including HIF, NF-kB, and p53. It is often mis-expressed in many human cancers and has been shown to promote stem cell-like characteristics in malignant cells, in part, due to the inhibitory role of Ing4 in the NF-kB signaling pathway. The transcription factor NF-kB is a regulator of inflammatory response and serves an important role in embryonic HSPC emergence, survival, differentiation and proliferation. The Ing4 protein binds to the p65/RelA subunit of NF-kB, inhibiting DNA binding and suppressing NF-kB cytokines and inflammatory pathways. In the absence of Ing4 there is an overexpression of NF-kB target genes that have inhibitory effects on hematopoietic programming. Given the regulatory role of Ing4 in both hematopoiesis and cancer, it is likely critical to the regulation of stem cell self-renewal, maintenance and specialization. To better define the role of Ing4 on hematopoiesis we use two Ing4 loss-of-function models: zebrafish and mouse. For the zebrafish model of Ing4 deficiency, Ing4-deficient zebrafish embryos lose >90% of runx1+/c-myb+ cells in the aorta, gonad, mesonephros (AGM) region of the developing zebrafish embryo, demonstrating a lack of HSPC specification. 36 hours post fertilization (hpf) Ing4 morphants display increased expression of NF-kB target genes when Ing4 is absent. Genetic epistasis experiments performed to block translation of RelA, IL-1b, and additional NF-kB target gene mRNA revealed recovered HSC marker expression in the aorta. To discover small molecule inhibitors that would mimic these effects, we conducted an in vivo chemical screen of NF-kB pathway inhibitors assessing their ability to rescue HSC specification in Ing4 morphant zebrafish. Ing4 morphants treated with NF-kB inhibitors had reduced NF-kB cytokine expression, as well as a dose-dependent rescue of HSC marker expression in the aorta. These results suggest that NF-kB inhibition could remediate the effects of Ing4 loss on hematopoiesis. To more thoroughly profile the effects of Ing4 loss on HSC specification and the bone marrow niche, an Ing4-/-mouse model was used. These mice are developmentally normal but are hypersensitive to stimulation with LPS due to increased inflammatory signaling. Peripheral blood analysis reveals an increase in Mac-1 cells in the Ing4-/- mouse. Ing4-/- bone marrow progenitors are skewed toward granulocyte-myocyte progenitor cells (GMPs) lending to the shift in cell populations present in the peripheral blood. Ing4 loss further disrupts the mouse hematopoietic program resulting in a dramatic increase in the number of short term-HSCs (ST-HSC) (WT: 11.4%, Null: 31.7%), a modest increase in long term-HSCs (LT-HSC) (WT: 2.4%, Null: 5.52%), and a dramatic decrease in multipotent progenitors (MPPs) (WT: 47.9%, Null: 19.3%). We also found significant alterations in stress hematopoiesis following competitive HSC transplant where sorted Ing4-/- LT-HSCs failed to engraft. Following myeloablative insult, we found no significant change in Ing4-/- LT-HSC (-1.18%) when compared with ST-HSC (-14.43%) indicating reduced sensitivity to 5-FU ablation in the Ing4-/- LT-HSC group. Cell cycle analysis identified 92.9% of Ing4-/- LT-HSCs are in G0 compared to 76.2% of wildtype LT-HSCs. ST-HSCs were also more quiescent with 27% of Ing4-/- ST-HSCs in G0 compared to 11.1% of wildtype ST-HSCs. Previously published work reports hyper proliferative HSCs that exhibit loss of quiescence as a result of proinflammatory NF-kB signaling. We believe that the interaction between Ing4 and the HIF-1a pathway may play a role in the observed phenotype of Ing4-/- LT-HSCs resulting in increased quiescence and disruption of the balance between self-renewal and differentiation critical to reconstitution of the hematopoietic compartment. Overall, our findings suggest that the regulatory effects of Ing4 play a crucial role in hematopoiesis and provides key tools for further identification and characterization of Ing4 pathways and functions. Disclosures Zon: CAMP4 Therapeutics: Current equity holder in private company, Other: Founder; Fate Therapeutics: Current equity holder in publicly-traded company, Other: Founder; Scholar Rock: Current equity holder in publicly-traded company, Other: Founder; Amagma Therapeutics: Current equity holder in private company, Other: Founder; Cellarity: Consultancy; Celularity: Consultancy.

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DONAHUE, ROBERT E., STEVEN C. CLARK y ROBERT KAMEN. "Hematopoietic Growth Factors as Therapeutic Agents". Annals of the New York Academy of Sciences 511, n.º 1 Normal and Ne (diciembre de 1987): 10–16. http://dx.doi.org/10.1111/j.1749-6632.1987.tb36233.x.

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Estrov, Z., R. Kurzrock, M. Wetzler, H. Kantarjian, M. Blake, D. Harris, JU Gutterman y M. Talpaz. "Suppression of chronic myelogenous leukemia colony growth by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors: a novel application for inhibitors of IL-1 activity". Blood 78, n.º 6 (15 de septiembre de 1991): 1476–84. http://dx.doi.org/10.1182/blood.v78.6.1476.1476.

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Abstract In this study, we investigated the role of interleukin-1 beta (IL-1 beta) in the malignant evolution of chronic myelogenous leukemia (CML) and the functional activity of IL-1 inhibitors. Bone marrow (BM) and peripheral blood (PB) low-density cells from 38 CML patients were studied in the colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte colony culture assay. Samples from patients with early stage, interferon-alpha (IFN)-sensitive disease formed hematopoietic colonies in the presence of fetal calf serum (FCS), erythropoietin (Epo), and one of the following: granulocyte-macrophage colony- stimulating factor (10 ng/mL), IL-3 (15 ng/mL), both, or phytohemagglutinin-conditioned medium. The addition of IL-1 beta augmented IFN-sensitive CML colony growth in a dose-dependent manner at concentrations of 10 to 100 U/mL. In sharp contrast, addition of the above growth factors did not augment the colony growth-promoting effect of FCS and Epo in samples from IFN-resistant patients; further, adherent cell fractionation or T-lymphocyte depletion attenuated the “autonomous” colony growth. Lysates of 2.5 x 10(7) low-density cells from each of six IFN-resistant and six IFN-sensitive CML patients and three normal volunteers were tested for intrinsic IL-1 beta content in an enzyme-linked immunosorbent assay and yielded a mean of 610 pg, 54.6 pg, and 49.4 pg of IL-1 beta, respectively (P less than .045). Interestingly, both soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) at concentrations of 5 to 100 ng/mL (sIL-1R) and 10 to 500 ng/mL (IL-1RA) inhibited CML colony growth in a dose-dependent fashion, with maximal inhibition of 64% and 65%, respectively. A similar effect was noted with the use of anti-IL-1 beta neutralizing antibodies. These data implicate IL-1 beta in CML disease progression and suggest that the inhibitory effects of molecules such as sIL-1R and IL-1RA could conceivably be the basis of a novel therapeutic strategy against this disorder.

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34

Estrov, Z., R. Kurzrock, M. Wetzler, H. Kantarjian, M. Blake, D. Harris, JU Gutterman y M. Talpaz. "Suppression of chronic myelogenous leukemia colony growth by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors: a novel application for inhibitors of IL-1 activity". Blood 78, n.º 6 (15 de septiembre de 1991): 1476–84. http://dx.doi.org/10.1182/blood.v78.6.1476.bloodjournal7861476.

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In this study, we investigated the role of interleukin-1 beta (IL-1 beta) in the malignant evolution of chronic myelogenous leukemia (CML) and the functional activity of IL-1 inhibitors. Bone marrow (BM) and peripheral blood (PB) low-density cells from 38 CML patients were studied in the colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte colony culture assay. Samples from patients with early stage, interferon-alpha (IFN)-sensitive disease formed hematopoietic colonies in the presence of fetal calf serum (FCS), erythropoietin (Epo), and one of the following: granulocyte-macrophage colony- stimulating factor (10 ng/mL), IL-3 (15 ng/mL), both, or phytohemagglutinin-conditioned medium. The addition of IL-1 beta augmented IFN-sensitive CML colony growth in a dose-dependent manner at concentrations of 10 to 100 U/mL. In sharp contrast, addition of the above growth factors did not augment the colony growth-promoting effect of FCS and Epo in samples from IFN-resistant patients; further, adherent cell fractionation or T-lymphocyte depletion attenuated the “autonomous” colony growth. Lysates of 2.5 x 10(7) low-density cells from each of six IFN-resistant and six IFN-sensitive CML patients and three normal volunteers were tested for intrinsic IL-1 beta content in an enzyme-linked immunosorbent assay and yielded a mean of 610 pg, 54.6 pg, and 49.4 pg of IL-1 beta, respectively (P less than .045). Interestingly, both soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) at concentrations of 5 to 100 ng/mL (sIL-1R) and 10 to 500 ng/mL (IL-1RA) inhibited CML colony growth in a dose-dependent fashion, with maximal inhibition of 64% and 65%, respectively. A similar effect was noted with the use of anti-IL-1 beta neutralizing antibodies. These data implicate IL-1 beta in CML disease progression and suggest that the inhibitory effects of molecules such as sIL-1R and IL-1RA could conceivably be the basis of a novel therapeutic strategy against this disorder.

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Kumar, Narendra, Longxiang Kuang, Ryan Villa, Priyam Kumar y Jayshree Mishra. "Mucosal Epithelial Jak Kinases in Health and Diseases". Mediators of Inflammation 2021 (16 de marzo de 2021): 1–17. http://dx.doi.org/10.1155/2021/6618924.

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Janus kinases (Jaks) are a family of nonreceptor tyrosine kinase that include four different members, viz., Jak1, Jak2, Jak3, and Tyk2. Jaks play critical roles in immune cells functions; however, recent studies suggest they also play essential roles in nonimmune cell physiology. This review highlights the significance of epithelial Jaks in understanding the molecular basis of some of the diseases through regulation of epithelial-mesenchymal transition, cell survival, cell growth, development, and differentiation. Growth factors and cytokines produced by the cells of hematopoietic origin use Jak kinases for signal transduction in both immune and nonimmune cells. Among Jaks, Jak3 is widely expressed in both immune cells and in intestinal epithelial cells (IECs) of both humans and mice. Mutations that abrogate Jak3 functions cause an autosomal severe combined immunodeficiency disease (SCID) while activating Jak3 mutations lead to the development of hematologic and epithelial cancers. A selective Jak3 inhibitor CP-690550 (Xeljanz) approved by the FDA for certain chronic inflammatory conditions demonstrates immunosuppressive activity in rheumatoid arthritis, psoriasis, and organ transplant rejection. Here, we also focus on the consequences of Jak3-directed drugs on adverse effects in light of recent discoveries in mucosal epithelial functions of Jak3 with some information on other Jaks. Lastly, we brief on structural implications of Jak3 domains beyond the immune cells. As information about the roles of Jak3 in gastrointestinal functions and associated diseases are only just emerging, in the review, we summarize its implications in gastrointestinal wound repair, inflammatory bowel disease, obesity-associated metabolic syndrome, and epithelial cancers. Lastly, we shed lights on identifying potential novel targets in developing therapeutic interventions of diseases associated with dysfunctional IEC.

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Nii, Takenobu, Tomotoshi Marumoto, Hirotaka Kawano, Saori Yamaguchi, Yoko Nagai, Jiyuan Liao, Michiyo Okada, Yoshie Miura y Kenzaburo Tani. "Efficient Hematopoietic Differentiation of Common Marmoset Embryonic Stem Cells by the Inhibition of Their Self-Renewal Pathway." Blood 120, n.º 21 (16 de noviembre de 2012): 2311. http://dx.doi.org/10.1182/blood.v120.21.2311.2311.

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Abstract Abstract 2311 The human regenerative medicine by the transplantation of the functional cells differentiated from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) have great potential of contributing to the treatments for various diseases, and thus have attracted huge public attention. However, the risk of unwelcome tumor formation originated from transplanted cells in recipients remains to be solved. Therefore the safety and efficacy of ESC/iPSC-based therapies should be carefully evaluated using reliable animal disease models before their clinical application. Among experimental animal models, common marmoset (CM, Callithrix jacchus), one of NEW WORLD monkeys, has recently been recognized as a useful non-human primate because they are small, easy to handle, highly reproductive and genetically very similar to humans. We have continuously investigated the characteristics of ESCs and iPSCs derived from CM. Understanding the self-renewal pathways in ESCs/iPSCs is crucial for the development of improved technology to culture and differentiate them into functional cells of potential therapeutic use. It has been reported that the maintenance of self-renewal in human or mouse ESCs/iPSCs require basic fibroblast growth factor (bFGF) or leukemia Inhibitory factor (LIF) respectively, however the growth factors required for the culture of CM ESCs/iPSCs have not been clearly determined. To clarify whether LIF or bFGF is more appropriate to maintain self-renewal of CM ESCs in culture, we examined the proliferation rate of CM40, a CM ESC line, maintained in the presence or absence of LIF or bFGF. CM ESCs were passaged at a ratio of 1:3 every 3 to 4 days. We found that the number of OCT3/4+cells was significantly increased by the addition of bFGF but not of LIF compared to control (w/o cytokines). Similar results were obtained when Cj11, another CM ESC line, was used. These results indicate that bFGF is essential for culturing CM ESCs, but LIF is dispensable. It has been reported that bFGF and its downstream PI3K-AKT and MEK-ERK pathways are important for maintenance of ESCs in human. Thus we examined whether PI3K-AKT and MEK-ERK pathway play crucial roles in the maintenance of self-renewal in CM ESCs. CM40 was cultured in the medium containing bFGF in the presence of PI3K inhibitor (LY294002) or MEK inhibitor (PD0325901). We found that the percentage and number of OCT3/4+ cells were gradually decreased in the presence of LY294002 (10 μM or 20 μM), suggesting that PI3K-AKT pathway is essential for the self-renewal of CM ESCs. Furthermore, the percentage and number of OCT3/4+cells were gradually decreased by addition of PD0325901 (1 μM or 5 μM) in the course of 4 passages, indicating that MEK-ERK pathway also plays a role in the self-renewal of CM ESCs. Next we examined if inhibition of self-renewal pathway such as PI3K-AKT or MEK-ERK promote hematopoietic differentiation in CM ESCs. One of methods for inducing hematopoietic cells from ESCs is embryoid body (EB) formation which is a conventional technique frequently used for in vitro differentiation of ESCs. Thus to induce hematopoietic differentiation, we performed EB formation assay by plating single-cell suspension of CM ESCs (3 × 105 cells) in StemLine II supplemented with 50 ng/ml BMP4 and 50 ng/ml VEGF with or without 10 μM LY294002 or 5 μM PD0325901 for 2 days. Then we removed half the medium and added fresh medium with the same final concentrations of BMP4, VEGF, LY294002 and PD0325901, plus 25 ng/ml SCF, 25 ng/ml TPO and 25 ng/ml FLT3L to expand the hematopoietic progenitors. We found that addition of LY294002 or PD0325901 increased the population of cells positive for CD34, a marker for hematopoietic stem/progenitor and endothelial cells, in day4-EBs. These CD34+cells showed hematopoietic differentiation potential proved by colony forming unit (CFU) assay Taken together, inhibition of self-renewal pathway such as PI3K-AKT or MEK-ERK in CM ESCs is thought to promote their hematopoietic differentiation by EB formation. Our findings might be useful to develop a better technology of the culture and hematopoietic differentiation of CM ESCs as well as to test efficacy and safety of ESC-derived hematopoietic cells using CM disease models for the future ESC/iPSC-based human regenerative medicine. Disclosures: No relevant conflicts of interest to declare.

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37

Ganser, Arnold y Meinolf Karthaus. "Clinical use of hematopoietic growth factors". Current Opinion in ONCOLOGY 8, n.º 4 (julio de 1996): 265–69. http://dx.doi.org/10.1097/00001622-199607000-00001.

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Sunthankar, Kathryn I., Benjamin J. Reisman, Candace H. Cote y Paul Brent Ferrell. "Single Cell Signaling Responses Stratify Immune and Leukemia Cell Populations in Acute Myeloid Leukemia". Blood 134, Supplement_1 (13 de noviembre de 2019): 2680. http://dx.doi.org/10.1182/blood-2019-129602.

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In healthy hematopoiesis, cell identity and signaling response are tightly linked, with predictable cell type-specific responses to cytokines and growth factors. However, this correlation is often disrupted in myeloid malignancies, including acute myeloid leukemia (AML), wherein signaling responses may be driven directly by kinase mutational activation or cell state changes due to epigenetic alterations, for instance. In order to resolve ligand-driven signaling pathways in bone marrow, tools that allow simultaneous phenotypic characterization and functional cellular responses at single cell resolution are needed. Here, we present the use of a high content mass cytometry panel combined with mass-tag cell barcoding in order to characterize cell identity and signaling responses in bone marrow hematopoietic cells from healthy donors and leukemic patients. We created a phospho-specific mass cytometry panel comprising 24 surface phenotyping markers to resolve the predominant cellular subsets within bone marrow and blood. We perturbed cellular signaling with nine growth factors, cytokines, and chemicals and measured immediate (15 minute) responses at 10 intracellular signaling markers (pSTAT1, pSTAT3, pSTAT5, pSYK, pp38, pERK1/2, pS6, pNFkB, IkBa, & pAKT). To improve robustness of the signaling response analysis, we used mass-tag cell barcoding with palladium prior to surface and intracellular antibody staining, followed by computational debarcoding. Downstream analysis was performed with Cytobank and R. The data set included thirty-five AML patient samples and seven healthy controls with greater than 300,000 cells collected over the 10 barcoded conditions (unstimulated and 9 stimulation conditions). Dimensionality reduction with uniform manifold approximation and projection (UMAP) combined with topological clustering (HDBSCAN) enabled initial data analysis and was followed by expert identification of resultant clusters via surface marker expression. Density-based clustering of the common UMAP embedding of all samples identified known subsets of hematopoietic cells (B cells, CD4 (CD25+ and CD25-) and CD8 T cells, double negative (DN) T cells, NK cells (three subsets), erythroblasts, several subsets of myeloid and leukemia cells, and hematopoietic stem cells (HSCs)). Mass-tag cell barcoding provided stable UMAP embeddings for each sample over the 10 stimulation conditions. High dimensional signaling response was calculated per cell and per each major cell subset for the 90 nodes (9 conditions by 10 markers) and hierarchical clustering stratified samples based upon signaling signatures. Signaling responses varied across non-leukemia and leukemia cell populations in AML samples, whereas cellular phenotypes were more well correlated with signaling phenotypes in healthy samples. Heterogeneity in signaling response was driven by variability seen in several "stimulation:response" pairs. The most impactful pairs to clustering of AML blasts were IFNγ:pSTAT1, GM-CSF:pSTAT5, IL-3:pSTAT5, PMA:pS6, and IL-6:pSTAT3. Favorable risk samples (by European LeukemiaNet risk stratification) were found to have significantly larger pSTAT5 increases to IL-3 and GM-CSF than both intermediate and adverse risk subgroups. In CD8 T cells, responsiveness to PMA and IL-10 drove clustering, and, in particular, samples with ELN adverse risk showed reduced PMA:pS6 and PMA:pERK responses. We present a robust evaluation of intracellular signaling responses in the bone marrow cellular environment of AML. These data provide rationale for ongoing investigation aimed at targeting both leukemia and non-leukemia cell signaling pathways in the treatment of AML. Disclosures Ferrell: Incyte: Research Funding; Forma Therapeutics: Research Funding; Agios: Consultancy; Astex Pharmaceuticals: Research Funding.

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39

Waldmann, Thomas A., Ronald Levy y Barry S. Coller. "Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy". Hematology 2000, n.º 1 (1 de enero de 2000): 394–408. http://dx.doi.org/10.1182/asheducation.v2000.1.394.20000394.

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This article focuses on the recent dramatic advances in the applications of monoclonal antibody therapy to hematopoietic and neoplastic disease. The increase in the understanding of the role of growth factors and their receptors in the pathogenesis of malignancy and other undesirable hematological events taken in conjunction with the ability to produce humanized chimeric monoclonal antibodies to these targets is providing a new perspective for the treatment of leukemia, lymphoma and breast cancer, autoimmune disease and for prevention of ischemic complications. Dr. Waldmann describes approaches targeting the Her2/neu and the II-2/IL-15 receptor systems. The Her2/neu receptor is overexpressed in select breast, ovarian, gastric and pancreatic neoplasms. The use of trastuzumab (Herceptin) in the treatment of patients with breast cancer whose tumors overexpress this receptor are reviewed. The IL-2 receptor (Tac) is expressed on select malignant cells (adult T cell leukemia, hairy cell leukemia) and activated T cells involved in autoimmune disease and organ rejection. Humanized anti-Tac alone (daclizumab, Zenapax) or armed with toxins or radionuclides have been used successfully in the treatment of leukemia. Dr. Levy updates the experience with rituximab targeting CD20 on B cell lymphomas and reviews the antibodies to CD3, CD22, CD33, CD52, HLA-DR β chain and HLA-D currently in or proposed for clinical trials, including radiolabelled antibodies. In the last section, Dr. Coller reviews the therapeutic results achieved with abciximab (ReoPro), an antagonist of platelet receptor GPIIbIIIa for the prevention of restenosis in percutaneous coronary interventions and the treatment of unstable angina. The mechanism of action, pharmacology and safety and efficacy of abciximab are reviewed.

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40

Waldmann, Thomas A., Ronald Levy y Barry S. Coller. "Emerging Therapies: Spectrum of Applications of Monoclonal Antibody Therapy". Hematology 2000, n.º 1 (1 de enero de 2000): 394–408. http://dx.doi.org/10.1182/asheducation.v2000.1.394.394.

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Abstract This article focuses on the recent dramatic advances in the applications of monoclonal antibody therapy to hematopoietic and neoplastic disease. The increase in the understanding of the role of growth factors and their receptors in the pathogenesis of malignancy and other undesirable hematological events taken in conjunction with the ability to produce humanized chimeric monoclonal antibodies to these targets is providing a new perspective for the treatment of leukemia, lymphoma and breast cancer, autoimmune disease and for prevention of ischemic complications. Dr. Waldmann describes approaches targeting the Her2/neu and the II-2/IL-15 receptor systems. The Her2/neu receptor is overexpressed in select breast, ovarian, gastric and pancreatic neoplasms. The use of trastuzumab (Herceptin) in the treatment of patients with breast cancer whose tumors overexpress this receptor are reviewed. The IL-2 receptor (Tac) is expressed on select malignant cells (adult T cell leukemia, hairy cell leukemia) and activated T cells involved in autoimmune disease and organ rejection. Humanized anti-Tac alone (daclizumab, Zenapax) or armed with toxins or radionuclides have been used successfully in the treatment of leukemia. Dr. Levy updates the experience with rituximab targeting CD20 on B cell lymphomas and reviews the antibodies to CD3, CD22, CD33, CD52, HLA-DR β chain and HLA-D currently in or proposed for clinical trials, including radiolabelled antibodies. In the last section, Dr. Coller reviews the therapeutic results achieved with abciximab (ReoPro), an antagonist of platelet receptor GPIIbIIIa for the prevention of restenosis in percutaneous coronary interventions and the treatment of unstable angina. The mechanism of action, pharmacology and safety and efficacy of abciximab are reviewed.

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41

Rowe, A., J. Eberhard y J. Sanchez-Ramos. "Hematopoietic growth factors: Novel therapeutic strategy for Alzheimer's disease". Drugs of the Future 34, n.º 12 (2009): 977. http://dx.doi.org/10.1358/dof.2009.034.12.1416991.

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42

Hayakawa, Fumihiko, Keiki Sugimoto, Shingo Kurahashi, Hironori Matsuyama, Yasuo Harada, Norikazu Hashimoto, Naoto Ohi et al. "A Novel Direct STAT3 Inhibitor OPB-31121 Induces Tumor-Specific Growth Inhibition In a Wide Range of Hematopoietic Malignancies and Effectively Suppresses the Chemotherapy Resistant Quiescent Cells In Vivo". Blood 116, n.º 21 (19 de noviembre de 2010): 3277. http://dx.doi.org/10.1182/blood.v116.21.3277.3277.

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Abstract Abstract 3277 Signal Transduction and Activator of Transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate a wide range of biological processes such as cell proliferation, apoptosis, differentiation, development, and immune response. Stimulation with cytokines or growth factors results in the tyrosine phosphorylation of STAT proteins via activation of upstream tyrosine kinases like Janus kinase (JAK) family kinases. Activated STAT proteins translocate to the nucleus and regulate gene expression through direct binding to the promoters of responsive genes. STAT3 is widely recognized as being a master regulator of the cellular functions that lead to the cancer phenotype. Constitutive activation of STAT3 is observed in a broad spectrum of human cancers and induces uncontrolled cell proliferation and apoptosis-resistance. It has been identified as a promising target for anti-tumor drug, but to date most of the trials to block STAT-signaling were the inhibition of upstream kinases like JAK family kinases, especially in clinical trials. Here, we report a novel STAT3 inhibitor, OPB-31121, that has no inhibitory effect on kinases including JAK family kinases. OPB-31121 treatment of HEL92.1.7 cells that had constitutive active mutation of JAK2 inhibited phosphorylation of STAT3 without inhibition of JAK2 phosphorylation (Figure A). STAT3 phosphorylation by JAK2 in vitro was also inhibited by OPB-31121 under constant JAK2 autophosphorylation. On the other hand, it did not inhibit dimerization and nuclear translocation of STAT3 once STAT3 was phosphorylated. Also, direct association between OPB-31121 and STAT3 was suggested in vitro. These data implies that one of the mechanisms of OPB-31121 action was the direct inhibition of STAT3 phosphorylation without JAK kinase inhibition. OPB-31121 demonstrated strong growth suppressive effect (IC50 < 10 nM) in cell lines of a wide range of cancer especially hematopoietic malignancies including acute myeloid leukemia (AML) with JAK2 mutation or fms-related tyrosine kinase 3 (FLT3) mutation, chronic myeloid leukemia (CML), and myeloma. It is revealed that STAT3 is constitutively activated by tyrosine kinase signal from oncoprotein or oncogenic autocrine of IL-6 pathway in these cell lines. Of note, OPB-31121 had little growth inhibitory effect on normal hematopoietic cells and hardly affected colony formation of human cord blood cells at 100 nM. We also demonstrated growth suppression or regression of cell lines including HEL92.1.7, KU812 (CML), and TCCy/sr (ALL positive for BCR-ABL with T315I mutation) in NOD/SCID mice (T/C: 1.8 to 39.5 %). For further analyses, we used human leukemia model mouse where clinical samples of human leukemia were transplanted into NOD/SCID/IL2-Rgammac−/− (NOG) mice and could be maintained by serial transplantation. In this system, heterogeneity and hierarchy of differentiation of leukemia cells, if they had, are maintained. OPB-31121 induced significant growth suppression of leukemia cells of BCR-ABL-positive acute lymphoblastic leukemia (ALL), CML-blast crisis (BC), CML-BC with T315I mutation in BCR-ABL, and AML with FLT3/ITD (T/C: 4 to 58 %, Figure B). Furthermore, treatment with cytarabine induced accumulation of quiescent cells that were thought to be relatively resistant to chemotherapy, whereas OPB-31121 did not cause such accumulation, suggesting its effectiveness on quiescent cells (Figure C). We are now investigating the effect of OPB-31121 on leukemia-initiating cells and the results will be shown at the meeting. Taken together, we conclude that OPB-31121 holds promise as a therapeutic agent against a wide range of hematopoietic malignancies. This drug is under phase 1 trial in Hong-Kong, Korea, and the USA. Disclosures: Hayakawa: Otsuka Pharmaceutical Co., Ltd.: Research Funding. Sugimoto:Otsuka Pharmaceutical Co., Ltd.: Employment. Matsuyama:Otsuka Pharmaceutical Co., Ltd.: Employment. Harada:Otsuka Pharmaceutical Co., Ltd.: Employment. Hashimoto:Otsuka Pharmaceutical Co., Ltd.: Employment. Ohi:Otsuka Pharmaceutical Co., Ltd.: Employment. Kodama:Otsuka Pharmaceutical Co., Ltd.: Employment. Sumida:Otsuka Pharmaceutical Co., Ltd.: Employment. Naoe:Chugai pharmaceutical, Zenyaku pharmaceutical, Kyowa-Kirin pharmaceutical, Dainippon-Sumitomo pharmaceutical, Novartis pharmaceutical, Janssen pharmaceutical, Otsuka pharmaceutical: Research Funding.

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43

Merchan Ruiz, Brayan Marcel, Teresa Bernal, Montserrat Arnan, Mar Tormo, Jose Angel Hernandez Rivas, Maria Calbacho, Rosa Coll et al. "IMPACT of Therapeutic Strategy and Time to Therapy Initiation on Clinical Evolution of Patients with NEWLY Diagnosed Chronic Myelomonocytic Leukemia. a Report from Erasme Study". Blood 124, n.º 21 (6 de diciembre de 2014): 5607. http://dx.doi.org/10.1182/blood.v124.21.5607.5607.

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Abstract Introduction Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder characterized by a heterogeneous clinical and morphological expression that shares features of both myelodysplastic syndromes (MDS) and chronic myeloproliferative disorders. In the last years therapy of CMML has undergone a change with the inclusion of the demethylating agents but data regarding their impact on the “real life” setting are still scarce. The aim of our study was to evaluate the use of the different therapies and the time to therapy in an unselected Spanish population within the ERASME study. Materials and methods The ERASME study (CEL-SMD-2012-01) is an observational, post-authorization, prospective, multicenter study that will include a total of 600 patients with MDS and CMML and follow them during a minimum of three years (or until death). The primary objective of this study is to describe the disease progression in routine clinical practice, based on the initial therapeutic strategy, in patients with newly diagnosed MDS and CMML. We present here the results of a pre-specified interim analysis with data of CMML patients enrolled in the ERASME study. Initial patient management strategy is classified in three groups: Observation (OB) & support (SP) (including blood and platelet transfusions and growth factors), active therapy (AT) (including chemotherapy, azacitidine, lenalidomide, etc) and allogenic hematopoietic cell transplant (HCT) (including those patients receiving other therapies before transplant). Results A total of 41 CMML patients (34% women) with a median age of 80 years (range 49-91) have been recruited between January 2013-June 2014. The median follow-up time was 6.7 months (range 0.4-15.1). Morphological subtypes according WHO classification were CMML-1 (blasts count <10%) in 35 patients (85%) and CMML-2 (blasts count 10% to 19%) in 6 (15%). According to FAB criteria, 30 patients (73%) had CMML-MD depending on absolute leukocyte count at diagnosis (WBC ≤13x109/L) and 11 (27%) had CMML-MP (WBC >13x109/L). Karyotype was normal in 32 patients (86%). Five patients displayed cytogenetic abnormalities; 3 out of 5 patients with trisomy 8 (isolated or with one additional abnormality). The CMML-GESMD cytogenetic risk classification was low/intermediate/high risk in 83%/10%/5% of patients, respectively. The CPSS was low/int-1/int-2/high in 46%/32%/15%/5% of patients, respectively. Nine out of 41 patients were transfusion dependent at diagnosis. Median bone marrow blast count was 3% (range 0-33). Hemoglobin, platelet and neutrophil count was: 11.1 g/dL (range 7.8-16.7), 106x103/µL (4.2-415), and 3.98x109/L (range 0.48-57.2), respectively. After diagnosis, 33, 7 and 1 of CMML patients were considered candidate to SP/OB, AT and HCT strategy, respectively. The main reasons for treatment selection were risk-disease (90%), symptomatology (83%), age (73%), and comorbidities (46%).The median time to AT initiation from diagnosis for AT/OB&SP was 0.52/2.5 months (range 0.22-2.29) and (range 1.0-4.7) for each group, respectively. Patients in active therapy received azacitidine (n=2, 29%), other low-dose chemotherapy (n=4, 57%) and other therapy (erythropoietin and azacitidine) (n=1, 14%), respectively. Only one patient was considered candidate for HCT and this patient received azacitidine prior the transplant. At last follow-up, a total of 5 (12%) of patients have died (2, 29% of active therapy and 3, 9% of support group) after a median of 3.6 months (range 3.1-4.1) and 1.7 months (range 0.7-10), for each group respectively. Conclusions CMML patients were treated on an individualized therapy strategy after diagnostic evaluation and prognosis assessment. More data on disease progression in routine clinical practice may be useful in characterizing the newly diagnosed CMML patients. Our prospective study confirms that azacitidine has been considered a therapy for CMML patients, including for HCT candidates. Disclosures Off Label Use: Vidaza, erythropoietin stimulating agents, revlimid. Valcarcel:Celgene: Honoraria, Speakers Bureau. Rafel:Celgene: Employment. Garcia:Celgene, Novartis: Consultancy, Speakers Bureau.

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Xie, Jingjing, Zhigang Lu y Chengcheng Zhang. "KBP-1 Supports Acute Myeloid Leukemia Development". Blood 126, n.º 23 (3 de diciembre de 2015): 1378. http://dx.doi.org/10.1182/blood.v126.23.1378.1378.

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Abstract Novel targets are needed to develop effective therapeutic approaches to treat acute myeloid leukemia (AML). We have developed a systematic strategy to identify factors important for leukemia development. We first use clinical databases to identify plasma membrane proteins that have correlations with the clinical outcomes of leukemia patients. We then validate the functions of candidate proteins in leukemia models and compare these functions to those in normal cells. The signaling pathways identified provide candidate targets for development of therapeutic approaches. Using this approach, we previously identified several ITIM-containing receptors that support AML development. Here we performed an in silico analysis of the relationship between gene expression and the overall survival of AML patients using data from three independent databases: the TCGA AML database (https://tcga-data.nci.nih.gov/tcga/; n = 187), the GSE6891 database (n = 520), and the GSE10358 database (n = 91). Expression of genes encoding several factors, including IL2RA, GPR56, ACDY7, and kappa-binding protein-1 (KBP-1), inversely correlated with the overall survival of AML patients. We focused on the potential function of KBP-1 in AML development in this study. KBP-1 is a transcriptional regulator that was known to inhibit NF-kB signaling and enhance TGF-beta signaling. Previous studies indicated that KBP-1 inhibits teratoma growth. We detected significantly higher kbp-1 mRNA levels in cells from human AML cells than other leukemia cells. To study the potential function of KBP-1 in human leukemia, we inhibited the expression of KBP-1 by introducing lentivirus-encoded shRNAs into MV4-11 and THP-1 cells. The KBP-1 deficiency resulted in significantly decreased in vitro growth of these leukemia cells over time. To determine the underlying mechanism by which KBP-1 supports the growth of leukemia cells, we compared the cell cycle status, migration, and apoptosis of AML cells treated with these shRNAs or scrambled control shRNA. KBP-1-deficient cells had significantly increased levels of apoptosis compared to cells treated with the control shRNA (for example, 68% early apoptosis in KBP-1 knockdown MV4-11 cells vs 15% early apoptosis in control MV4-11 cells at 3 days after shRNA infection). These results indicate that KBP-1 supports leukemia cell growth by suppressing apoptosis. We further studied the function of KBP-1 in AML development using the KBP-1 knockout mice and retrovirus transplantation mouse models. Consistent with the results of KBP-1 knockdown in human leukemia cells, the knockout of KBP-1 in MLL-AF9 AML cells dramatically delayed AML development in mice, as determined by survival, flow cytometry, immunohistochemistry, and colony forming analyses. Serial transplantation of wild-type and KBP-1 knockout AML cells indicates that KBP-1 deficiency impaired the self-renewal of AML stem cells. We are working on elucidating the underlying mechanism by which KBP-1 supports the activity of AML stem cells. Together, this is the first demonstration of KBP-1 function in hematopoietic maligancies. KBP-1 is highly expressed by AML cells and its expression correlates with AML development. KBP-1 supports the survival of human AML cells and the activity of AML stem cells. The tumor-supportive role of KBP-1 in AML is different from its tumor-suppressive function in teratoma. Disclosures No relevant conflicts of interest to declare.

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45

Nemunaitis, John. "Use of hematopoietic growth factors in marrow transplantation". Current Opinion in Oncology 6, n.º 2 (marzo de 1994): 139–46. http://dx.doi.org/10.1097/00001622-199403000-00005.

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&NA;. "Clinical use of hematopoietic growth factors and myelosuppression". Current Opinion in ONCOLOGY 8, n.º 4 (julio de 1996): B105–113. http://dx.doi.org/10.1097/00001622-199607000-00013.

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47

Gale, Robert Peter y Anna Butturini. "Use of hematopoietic growth factors in radiation accidents". International Journal of Radiation Oncology*Biology*Physics 19, n.º 5 (noviembre de 1990): 1291–95. http://dx.doi.org/10.1016/0360-3016(90)90247-h.

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48

Laver, J. y M. A. S. Moore. "Clinical Use of Recombinant Human Hematopoietic Growth Factors". JNCI Journal of the National Cancer Institute 81, n.º 18 (20 de septiembre de 1989): 1370–82. http://dx.doi.org/10.1093/jnci/81.18.1370.

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49

Dybko, Jaroslaw, Donata Urbaniak-Kujda, Katarzyna Kapelko-Slowik y Kazimierz Kuliczkowski. "Coexpression of Bmi-1 and Interleukin-3 Receptor Alpha Chain (CD123) Correlate with Poor Prognosis In Acute Myeloid Leukemia". Blood 116, n.º 21 (19 de noviembre de 2010): 4324. http://dx.doi.org/10.1182/blood.v116.21.4324.4324.

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Abstract Abstract 4324 Introduction Acute myeloid leukemia (AML) is characterized by the accumulation of immature cells due to disturbed differentiation and proliferation of the myeloid lineage. The traditional AML classification based on morphology, immunophenotyping, and cytogenetic abnormalities is not perfect, in part, because the leukemic population is functionally heterogeneous. AML cells comprise leukemic stem cells (LSCs) and mature leukemia cells that have differentiated abnormally. There has been a recent effort to identify new markers underlying this functional heterogeneity. Bmi-1 is a member of the Polycomb-group (PcG) proteins and is thought to inhibit inhibits cellular senescence and apoptosis. Bmi-1 was also recognized as an essential regulator of the self-renewal capabilities of both hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs). Additional markers of LSCs have been described recently. One of these, interleukin-3 receptor alpha chain (CD123) expressed on AML cells caused higher cycling activity and resistance to apoptosis induced by the lack of growth factor. Coexpression of Bmi-1 and CD123 might be indicative of poor prognosis and might identify patients requiring aggressive therapeutic schedules. Patients and methods Cells lines used included two AML lines (HL-60 and KG-1a), one chronic myeloid leukemia in blast crisis (K562), and one pre-B acute lymphoblastic leukemia (SD-1). A cohort of 58 patients newly diagnosed with AML during the previous five years at our center. Patient BM samples were obtained during routine diagnostic procedures before antineoplastic chemotherapy was started. Diagnosis was based on morphology, cytochemistry, and expression of leukocyte differentiation antigens. All patients were characterized by cytogenetics. Flow-cytometry was used to analyze bone marrow samples to identify Bmi-1+CD123+ population. Results Patient samples were divided into 2 groups. Patients in FAB subtypes M0 and M1 comprised group A (N = 20), and patients in all other subtypes comprised group B (N = 38). The median percentages of Bmi-1 positive cells and CD123 positive cells were higher in group A than in group B and healthy controls. There were significant differences in Bmi-1 expression between groups A and B (p = 0.002) and between healthy controls and all AML patients (p = 0.0007). There were no significance differences in CD123 expression between groups A and B but the percentage of CD123 positive cells in healthy controls was significantly lower than in all AML patients (p = 0.0001). Among all AML patients Bmi-1 expression and CD123 expression in CD34+ cells were highly correlated (R = 0.76, p = 0.001). Conclusions We thought it important to test coexpression of Bmi-1 and CD123 in the CD34 BM population of AML patients as these markers were both prognostic factors in AML. Our results showed that expression of these markers correlated and together provided an important predictor of prognosis in AML. The criteria of AML stratification are commonly known. However, CD123 and Bmi-1 could become “new” prognostic factors in AML as well as targets for therapeutic approaches. The facts that Bmi-1 is localized in the nucleus (Gil, et al 2005) and is expressed in both hematopoietic and leukemic stem cells (Lessard, et al 2003) makes the hypothetical use of Bmi-1-targeted inhibitors more complex. Thus, further investigation to refine prognosis and to optimize therapy of AML based on Bmi-1 expression in combination with other markers is needed. Disclosures: No relevant conflicts of interest to declare.

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Ruggeri, Loredana, Elena Urbani, Davide Chiasserini, Federica Susta, Pierluigi Orvietani, Emanuela Burchielli, Dunia Ramarli et al. "Alloreactive Natural Killer Cells Initiate a Unique Cellular and Molecular Pathway That Greatly Accelerates Immune Reconstitution after Allogeneic Bone Marrow Transplantation". Blood 128, n.º 22 (2 de diciembre de 2016): 548. http://dx.doi.org/10.1182/blood.v128.22.548.548.

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Abstract One outstanding issue in allogeneic hematopoietic transplantation is impaired immune reconstitution. As the primary site of T cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. Allogeneic hematopoietic transplantation may acutely damage the thymus through the chemo or radiotherapy, antibody therapy of the conditioning regime, infections acquired by the immunosuppressed patient, and thymic graft versus host disease. To date, attempts to improve thymic reconstitution have been disappointing. Pre-clinical experiments and pilot clinical trials tried to assess the role of a variety of therapeutic approaches, such as transfer of lymphoid progenitor cells, thymic grafts, or enhancement of thymopoiesis by administration of hormonal or cytokine/growth factor-based therapies, such as sex-steroid blockade, and IL-7, IL-22, KGF, or Flt-3 ligand administration (reviewed in Chaudhry et al., Immunol Rev. 2016). In mouse MHC mismatched transplantation models (F1 H-2d/b→parent H-2b), we previously found that infusion of donor versus recipient alloreactive NK cells eradicated recipient-type lympho-hematopoietic lineage cells, thereby enhancing engraftment, protecting from GvHD and eradicating leukemia (Ruggeri et al., Science 2002). Here, in the same models we show that infusion of alloreactive NK cells greatly accelerates the post-hematopoietic transplant recovery of donor-type immune cells, i.e., dendritic cells (DCs) (p<0.001), B lineage cells (p<0.001) and thymocytes (p<0.001) and maturation to B (p<0.001) and T cells (p<0.001). By the use of recipient chimeric mice displaying different tissue (i.e., hematopoietic vs non-hematopoietic) susceptibility to donor alloreactive NK cell killing, we show that a specific interaction between donor alloreactive NK cells and recipient DCs is responsible for the accelerated immune rebuilding. We find that donor-versus-recipient alloreactive NK cells trigger recipient DCs to synthesize a protein factor in a DNA translation-depended fashion (i.e., blocking DNA transcription in DCs abrogated the DC ability to produce the factor), and release it. Infusion of NK/DC co-culture supernatants containing this factor induced bone marrow and thymic stromal cells to produce IL-7 (p<0.001) and c-Kit ligand (p<0.001) and, thereby, the extraordinarily accelerated maturation of donor DCs, B- and T-cell precursors. Interestingly, in vitro experiments with human thymic stromal cells that support human thymocyte proliferation and differentiation demonstrated the exact same mechanisms. Supernatants from human alloreactive NK cell clones and human (HLA-class I KIR ligand mismatched) allogeneic DCs induced IL-7 production by human thymic stromal cells which in turn supported accelerated proliferation and maturation of human thymocytes (p<0.001). The murine and the human "immune rebuilding" factors displayed biochemical similarities as they both are highly hydrophobic 12KDa molecular weight proteins. Mass spectrometry analysis by stable isotope labeling with amino acids in cell culture (SILAC) identified Beta-2 Microglobulin (B2M) as the newly synthesized protein sharing the above biochemical features and present both in murine and human samples. B2M-KO mice used as recipients of MHC mismatched bone marrow transplant and given donor versus recipient alloreactive NK cells were unable to undergo accelerated immune rebuilding. However, their defect was repaired and accelerated rebuilding of donor-type DCs (p<0.001), B lineage cells (p<0.001) and thymocytes (p<0.001) was restored by the administration of culture supernatants obtained from alloreactive NK cells and wild-type (non-KO) MHC mismatched DCs. Finally, RNA interference experiments that silenced the B2M gene in human DCs resulted in loss of biological activity of supernatants obtained from alloreactive NK cells and B2M-silenced DCs. B2M plays a key role in the immune system as it is known to be part of MHC class I molecules. However, its role in signaling for immune precursor cell development has never been recognized. Here we report the discovery of a novel cellular and molecular pathway initiated by alloreactive NK cells and mediated by B2M that leads to greatly accelerated rebuilding of B and T cells after hematopoietic transplantation. Disclosures No relevant conflicts of interest to declare.

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