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1
Swatler, Julian, Laura Turos-Korgul, Ewa Kozlowska, and Katarzyna Piwocka. "Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias." Cancers 13, no. 6 (March 10, 2021): 1203. http://dx.doi.org/10.3390/cancers13061203.
Анотація:
Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.
2
Namikawa, R., R. Ueda, and S. Kyoizumi. "Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice." Blood 82, no. 8 (October 15, 1993): 2526–36. http://dx.doi.org/10.1182/blood.v82.8.2526.2526.
Анотація:
Abstract It has been shown previously that multilineage human hematopoiesis is maintained within human fetal bone marrow (BM) fragments implanted into severe combined immunodeficient (SCID) mice. We describe here an application of this animal model, the SCID-hu mouse, to the study of human myeloid leukemias. BM cells from 8 patients with various types of myeloid leukemias were injected directly into human bone grafts in the SCID-hu mouse. Cells from 7 patients grew in the human marrow without spreading to the mouse marrow. Cells from 6 of these patients were successfully transferred in vivo to secondary SCID-hu recipients. The surface phenotype and the cytologic features of the leukemia cells were conserved during passage in vivo. Thus, human myeloid leukemia cells could be reproducibly propagated in the human marrow environment in SCID-hu mice. The differentiation of promyelocytic leukemia cells in the SCID-hu mice was induced by all-trans retinoic acid, suggesting that the biologic features of the leukemia cells were maintained as well. Finally, evidence for a leukemic progenitor cell population in one case of acute myelogenous leukemia was provided with this system. This model may provide a useful tool for studying the biology of human myeloid leukemia as well as for evaluating new therapeutic modalities for myeloid leukemias.
3
Namikawa, R., R. Ueda, and S. Kyoizumi. "Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice." Blood 82, no. 8 (October 15, 1993): 2526–36. http://dx.doi.org/10.1182/blood.v82.8.2526.bloodjournal8282526.
Анотація:
It has been shown previously that multilineage human hematopoiesis is maintained within human fetal bone marrow (BM) fragments implanted into severe combined immunodeficient (SCID) mice. We describe here an application of this animal model, the SCID-hu mouse, to the study of human myeloid leukemias. BM cells from 8 patients with various types of myeloid leukemias were injected directly into human bone grafts in the SCID-hu mouse. Cells from 7 patients grew in the human marrow without spreading to the mouse marrow. Cells from 6 of these patients were successfully transferred in vivo to secondary SCID-hu recipients. The surface phenotype and the cytologic features of the leukemia cells were conserved during passage in vivo. Thus, human myeloid leukemia cells could be reproducibly propagated in the human marrow environment in SCID-hu mice. The differentiation of promyelocytic leukemia cells in the SCID-hu mice was induced by all-trans retinoic acid, suggesting that the biologic features of the leukemia cells were maintained as well. Finally, evidence for a leukemic progenitor cell population in one case of acute myelogenous leukemia was provided with this system. This model may provide a useful tool for studying the biology of human myeloid leukemia as well as for evaluating new therapeutic modalities for myeloid leukemias.
4
Aue, Georg, Yang Du, Susan M. Cleveland, Stephen B. Smith, Utpal P. Davé, Delong Liu, Marc A. Weniger, et al. "Sox4 cooperates with PU.1 haploinsufficiency in murine myeloid leukemia." Blood 118, no. 17 (October 27, 2011): 4674–81. http://dx.doi.org/10.1182/blood-2011-04-351528.
Анотація:
Abstract Cooperation of multiple mutations is thought to be required for cancer development. In previous studies, murine myeloid leukemias induced by transducing wild-type bone marrow progenitors with a SRY sex determining region Y-box 4 (Sox4)–expressing retrovirus frequently carried proviral insertions at Sfpi1, decreasing its mRNA levels, suggesting that reduced Sfpi1 expression cooperates with Sox4 in myeloid leukemia induction. In support of this hypothesis, we show here that mice receiving Sox4 virus-infected Sfpi1ko/+ bone marrow progenitors developed myeloid leukemia with increased penetrance and shortened latency. Interestingly, Sox4 expression further decreased Sfpi1 transcription. Ectopic SOX4 expression reduced endogenous PU.1 mRNA levels in HL60 promyelocytes, and decreased Sfpi1 mRNA levels were also observed in the spleens of leukemic and preleukemic mice receiving Sox4 virus-infected wild-type bone marrow cells. In addition, Sox4 protein bound to a critical upstream regulatory element of Sfpi1 in ChIP assays. Such cooperation probably occurs in de novo human acute myeloid leukemias, as an analysis of 285 acute myeloid leukemia patient samples found a significant negative correlation between SOX4 and PU.1 expression. Our results establish a novel cooperation between Sox4 and reduced Sfpi1 expression in myeloid leukemia development and suggest that SOX4 could be an important new therapeutic target in human acute myeloid leukemia.
5
Shvachko, L. P. "EMT-mechanizm induces the leukemic stemness phenotype in myeloid leukemias." Faktori eksperimental'noi evolucii organizmiv 23 (September 9, 2018): 256–60. http://dx.doi.org/10.7124/feeo.v23.1024.
Анотація:
Aim. To study the targeted expression EMT-induced markers N-cadherin, Snail and Twist in patients with the chronic and acute myeloid leukemias. Methods. RT-PCR, electroforesic in agarose gel, TotalLab v. 2.01 densitometry. Results. Have been investigated the relative levels of mRNA expression of N-cadherin and transcriptional factors Snail and Twist, associated with epithelial-to-mesenchymal induction (EMT) in patients with the essential polycytemia (EP), the chronic mieloid leukemia CML), the acute myeloid leukemia (AML) and the acute lymphoblastic leukemia (ALL). Conclusions. Have been highlighted the EMT stemness mechanism in Leukemic stem cell progression.
Keywords: the epithelial-to-mesencymal transition (EMT), EMT-inducer marker, N-cadherin, Snail, Twist, myeloid leukemias, leuklemic stem cell progression.
6
Jamieson, Catriona, Sidd Jaiswal, David Traver, Jason Gotlib, Mark Chao, and Irving L. Weissman. "Increased Expression of CD47 Is a Constant Marker in Mouse and Human Myeloid Leukemias." Blood 106, no. 11 (November 16, 2005): 3260. http://dx.doi.org/10.1182/blood.v106.11.3260.3260.
Анотація:
Abstract CD47, also known as integrin associated protein, is a ubiquitously expressed cell surface glycoprotein that interacts with a number of integrins, modulating leukocyte adhesion, migration, cell motility and platelet activation. CD47 is also the ligand for the macrophage inhibitory receptor signal regulatory protein α (SIRP α) and thus, impairs macrophage-mediated phagocytosis. Recent reports suggest that increased CD47 expression may play a role in the pathogenesis of lymphoproliferative disorders such as CLL (Mateo et al, Nat Med.1999; 5:1277) and multiple myeloma, and that a bivalent single-chain antibody fragment against human CD47 induces apoptosis of myeloma cells (Kikuchi et al, Leukemia Research2005; 29:445). However, little is known about the role of CD47 in the pathogenesis of myeloid leukemias or the stage of hematopoiesis at which CD47 is expressed. In order to identify the stage of hematopoiesis at which alterations in CD47 arise and its role in the pathogenesis of myeloid leukemias, we analyzed CD47 expression in hematopoietic stem cells (HSC), progenitors, and lineage-positive cells derived from three mouse transgenic models of myeloid leukemia including: 1) mice homozygous for overexpression of human bcl-2 in the myeloid lineage (hMRP8 bcl-2 x bcl-2); 2) mice deficient in Fas together with myeloid targeted overexpression of bcl-2 (Faslpr/lpr hMRP8 bcl-2); and 3) mice with both human bcl-2 and BCR-ABL targeted to the myeloid lineage (hMRP8-BCR-ABLxhMRP8-bcl-2). Quantitative RT-PCR analysis demonstrated a 3.01+/− 1.54 fold increase in CD47 transcripts in leukemic compared with control (bcl2+) bone marrow (normalized to b-actin) while FACS analysis revealed approximately a 10-fold increase in CD47 protein expression, as measured by mean fluorescence intensity (MFI), in leukemic GMP compared with wild type GMP. Moreover, transplantation experiments revealed that all mice with both primary (n=14 mice) and secondary (n=19 mice) leukemic transplantation potential had an expansion of granulocyte-macrophage progenitors (GMP) with high level CD47 expression. Human CD47 expression analysis was performed via FACS on human normal, pre-leukemic myeloproliferative disorder (MPD) or AML HSC, progenitors, and lineage positive cells derived from marrow or peripheral blood. MPD samples (n=63) included polycythemia vera (PV; n=15), post-polycythemic myeloid metaplasia/myelofibrosis (PPMM/MF; n=5), essential thrombocythemia (ET; n=8), atypical chronic myelogenous leukemia (aCML; n=2), CML (n=7), chronic eosinophilic leukemia (CEL; n=1), chronic myelomonocytic leukemia (CMML; n= 13) and acute myelogenous leukemia (AML; n=12). As noted with the transgenic leukemic mouse models, progression of human myeloproliferative disorders to AML (n=12) was associated with an expansion of the GMP pool (70.6% +/− S.D. 2.15) compared with normal bone marrow (14.7% +/− S.D. 2.3). Furthermore, FACS analysis revealed that CD47 expression first increased 1.7 fold in AML compared with normal HSC and then increased to 2.2 fold greater than normal with commitment of AML progenitors to the myeloid lineage. CD47 was over-expressed by AML primitive progenitors and their progeny but not by the majority of MPD (MFI 2.3+/−S.D. 0.43) compared with normal bone marrow (MFI 1.9 +/−S.D. 0.07). Thus, increased CD47 expression may serve as a useful diagnostic marker for progression to AML and may represent a novel therapeutic target.
7
ENACHE, Tatiana Cristina, Ana-Maria VLĂDĂREANU, Horia BUMBEA, Minodora ONISÂI, and Ion DUMITRU. "EPIDEMIOLOGICAL AND IMMUNOPHENOTYPIC CHARACTERIZATION OF ACUTE MYELOID LEUKEMIAS." Romanian Journal of Medical Practice 12, no. 4 (December 31, 2017): 234–39. http://dx.doi.org/10.37897/rjmp.2017.4.11.
Анотація:
Acute leukemias are a group of hematopoietic stem cell malignancies characterized by the proliferation and accumulation of immature cell (blasts) clones that associate medullary insufficiency syndrome (anemia, neutropenia, thrombocytopenia). Depending on the origin of the malignant clone, two major categories of acute leukemias are: acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML). Studies show an annual incidence of acute leukemias in European adults of 5-6 cases per 100,000 people with an increase in over 70 years of age, reaching an incidence of about 15-20 / 100,000 people. Of the total acute myeloid leukemias, 20% occur in children and 80% are among adults. Diagnosis of acute leukemias is based on the recognition of morphological, cytochemical, immunophenotypic, cytogenetic and molecular biology changes. Immunophenotyping plays a major role in the diagnosis and classification of acute leukemias, in differentiation of acute myeloid and lymphocytic leukemias and in detection of minimal residual disease.
8
Войцеховский, Валерий, Valeriy Voytsekhovskiy, Татьяна Заболотских, Tat'yana Zabolotskikh, Алексей Григоренко, Aleksey Grigorenko, Екатерина Филатова, and Ekaterina Filatova. "DAMAGE OF THE BRONCHOPULMONARY SYSTEM IN PATIENTS WITH CHRONIC HEMOBLASTOSIS." Bulletin physiology and pathology of respiration 1, no. 69 (October 5, 2018): 25–35. http://dx.doi.org/10.12737/article_5b975083a62278.59044240.
Анотація:
In 185 patients with chronic hemoblastosis (chronic lymphocytic leukemia, chronic myeloid leukemia, idiopathic myelofibrosis, multiple myeloma) after autopsy, the pathology of the bronchopulmonary system was studied. It was found out that in addition to immunodeficiency, an important role in the occurrence of respiratory diseases in chronic lymphocytic leukemia, as well as in chronic myeloid leukemia and idiopathic myelofibrosis in the stage of blast crisis is played by specific leukemic infiltration of the lungs, bronchi, pleura and diaphragm; the presence of leukostasis in the vessels of medium and small caliber with violation of microcirculation; compression of the diaphragm by significantly increased spleen and liver; in some cases (especially in chronic lymphocytic leukemia) hyperplasia of the lymphoid follicles of the bronchial tree. In chronic myeloid leukemia and idiopathic myelofibrosis, hyperthrombocytosis with the development of the sludge syndrome in small vessels of the lungs is essential. Pulmonary localization of inflammatory processes in patients with multiple myeloma is facilitated by lymphoid and plasma cell infiltration of the lungs, paraproteinosis of the lungs, localization of myeloma nodes in the ribs, lung tissue and bronchi.
9
Padmanabhan, Dr K. "An Interesting Case of Acute Myeloid Leukemia." Journal of Medical Science And clinical Research 05, no. 02 (February 28, 2017): 18166–68. http://dx.doi.org/10.18535/jmscr/v5i2.150.
10
Jones, Letetia, Sabina Sevcikova, Vernon Phan, Sachi Jain, Angell Shieh, Joshua Dubansky, Min Li, et al. "Myc Drives Chromosomal Gain in Acute Myeloid Leukemia." Blood 112, no. 11 (November 16, 2008): 792. http://dx.doi.org/10.1182/blood.v112.11.792.792.
Анотація:
Abstract Acute Myeloid Leukemia (AML) is a disease characterized by diverse genetic pathogenesis, including both balanced and unbalanced chromosomal aberrations. Much is known regarding the pathogenic effects of balanced rearrangements in AML, whereas our understanding of how unbalanced aberrations contribute to leukemia is more limited. The balanced t(15;17) chromosomal rearrangement is a nearly constant feature of acute promyeloctyic leukemia (APL), a subtype AML. The translocation fuses the promyelocytic leukemia gene (PML) to the retinoic acid receptor α gene (RARA). Trisomy 8 is the most common secondary karyotypic lesion observed in APL, and it has been speculated but not proven that the MYC gene contributes to this chromosomal gain. We previously reported that mouse chromosome 15, which contains the mouse Myc gene in a region syntenic to human chromosome 8q24, is commonly gained in the MRP8 PML-RARA mouse model of APL. We now report our work to assess the hypothesis that increased MYC cooperates with PML-RARα to accelerate disease and that gain of MYC/Myc drives +8 in humans and +15 in mice. Expressing MYC with a retroviral vector in PML-RARA bone marrow led to the rapid development of APL-like leukemias (3 months vs. 8.5 months with PML-RARA alone). Chromosome 15 was not gained in any of the leukemias, although 70% had other clonal karyotypic abnormalities. This finding suggests that when MYC is overexpressed, there is no selective pressure to gain chromosome 15, supporting our hypothesis that Myc is driving this gain. We also generated PML-RARA mice haploinsufficient for Myc to examine the effect of decreasing MYC levels. The median latency among leukemic animals was 258 days for mice with PML-RARA and two wild-type Myc alleles, whereas the latency was increased to 339 days for PML-RARA Myc haploinsufficient mice. Hence, lower MYC expression served as a check on leukemic transformation. Furthermore, the majority of the leukemias that arose in Myc haploinsufficient mice had gained wild-type Myc. These data demonstrate a selective pressure for Myc gain. Additional experiments showed that as MYC expression increases there is a decrease in both latency and genetic complexity of leukemias that arise, that MYC and PML-RARα interact to disrupt myeloid differentiation in vivo and that although MYC cooperates with PML-RARα to cause leukemia, additional events are required for completing transformation even at high levels of MYC. Altogether our studies of increased and decreased MYC expression in PML-RARA mice show a strong correlation between MYC dosage and leukemic transformation. Our results suggest that agents that target MYC might be useful for the treatment of AML.
11
Longo, Giuseppe S. A., Richard Gorlick, William P. Tong, Emine Ercikan, and Joseph R. Bertino. "Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells." Blood 90, no. 3 (August 1, 1997): 1241–45. http://dx.doi.org/10.1182/blood.v90.3.1241.
Анотація:
Abstract Previous work showed that acute myelocytic leukemia blasts accumulate less long chain polyglutamates of methotrexate (MTX) than acute lymphocytic leukemia blasts when incubated with this radiolabeled antifolate. This difference likely explains the increased sensitivity of lymphoid leukemias to short-term exposure of MTX as compared with myeloid leukemias. In this study, we examined the basis for differences between long chain MTX polyglutamate accumulation between different leukemia cell types using both leukemia cell lines and blasts freshly isolated from blood of leukemic patients. The major difference found between leukemia cells that accumulate long chain polyglutamates and those that do not were differences in Km values for the enzyme folylpolyglutamate synthetase. Km values did not change with partial purification of this enzyme, indicating that interfering substances in crude lysates were not responsible for this difference. We postulate that there may be differences in the properties of this enzyme related to tissue specific expression. In contrast to MTX, both Tomudex (Zeneca Pharmaceuticals, Wilmington, DE) and 1843U89, potent inhibitors of thymidylate synthetase, have low Kms for folylpolyglutamate synthetase, and polyglutamate forms of these inhibitors are accumulated to the same degree in both myeloid and lymphoid acute leukemia cells, paralleling the equivalent cytotoxicity found between myeloid and lymphoid leukemia cell lines. Based on these results, we believe a clinical trial of Tomudex in patients with acute myeloid leukemia is warranted.
12
Longo, Giuseppe S. A., Richard Gorlick, William P. Tong, Emine Ercikan, and Joseph R. Bertino. "Disparate Affinities of Antifolates for Folylpolyglutamate Synthetase From Human Leukemia Cells." Blood 90, no. 3 (August 1, 1997): 1241–45. http://dx.doi.org/10.1182/blood.v90.3.1241.1241_1241_1245.
Анотація:
Previous work showed that acute myelocytic leukemia blasts accumulate less long chain polyglutamates of methotrexate (MTX) than acute lymphocytic leukemia blasts when incubated with this radiolabeled antifolate. This difference likely explains the increased sensitivity of lymphoid leukemias to short-term exposure of MTX as compared with myeloid leukemias. In this study, we examined the basis for differences between long chain MTX polyglutamate accumulation between different leukemia cell types using both leukemia cell lines and blasts freshly isolated from blood of leukemic patients. The major difference found between leukemia cells that accumulate long chain polyglutamates and those that do not were differences in Km values for the enzyme folylpolyglutamate synthetase. Km values did not change with partial purification of this enzyme, indicating that interfering substances in crude lysates were not responsible for this difference. We postulate that there may be differences in the properties of this enzyme related to tissue specific expression. In contrast to MTX, both Tomudex (Zeneca Pharmaceuticals, Wilmington, DE) and 1843U89, potent inhibitors of thymidylate synthetase, have low Kms for folylpolyglutamate synthetase, and polyglutamate forms of these inhibitors are accumulated to the same degree in both myeloid and lymphoid acute leukemia cells, paralleling the equivalent cytotoxicity found between myeloid and lymphoid leukemia cell lines. Based on these results, we believe a clinical trial of Tomudex in patients with acute myeloid leukemia is warranted.
13
Swatler, Julian, Laura Turos-Korgul, Marta Brewinska-Olchowik, Sara De Biasi, Wioleta Dudka, Bac Viet Le, Agata Kominek, et al. "4-1BBL–containing leukemic extracellular vesicles promote immunosuppressive effector regulatory T cells." Blood Advances 6, no. 6 (March 17, 2022): 1879–94. http://dx.doi.org/10.1182/bloodadvances.2021006195.
Анотація:
Abstract Chronic and acute myeloid leukemia evade immune system surveillance and induce immunosuppression by expanding proleukemic Foxp3+ regulatory T cells (Tregs). High levels of immunosuppressive Tregs predict inferior response to chemotherapy, leukemia relapse, and shorter survival. However, mechanisms that promote Tregs in myeloid leukemias remain largely unexplored. Here, we identify leukemic extracellular vesicles (EVs) as drivers of effector proleukemic Tregs. Using mouse model of leukemia-like disease, we found that Rab27a-dependent secretion of leukemic EVs promoted leukemia engraftment, which was associated with higher abundance of activated, immunosuppressive Tregs. Leukemic EVs attenuated mTOR-S6 and activated STAT5 signaling, as well as evoked significant transcriptomic changes in Tregs. We further identified specific effector signature of Tregs promoted by leukemic EVs. Leukemic EVs-driven Tregs were characterized by elevated expression of effector/tumor Treg markers CD39, CCR8, CD30, TNFR2, CCR4, TIGIT, and IL21R and included 2 distinct effector Treg (eTreg) subsets: CD30+CCR8hiTNFR2hi eTreg1 and CD39+TIGIThi eTreg2. Finally, we showed that costimulatory ligand 4-1BBL/CD137L, shuttled by leukemic EVs, promoted suppressive activity and effector phenotype of Tregs by regulating expression of receptors such as CD30 and TNFR2. Collectively, our work highlights the role of leukemic extracellular vesicles in stimulation of immunosuppressive Tregs and leukemia growth. We postulate that targeting of Rab27a-dependent secretion of leukemic EVs may be a viable therapeutic approach in myeloid neoplasms.
14
Pietsch, T., U. Kyas, U. Steffens, E. Yakisan, MR Hadam, WD Ludwig, K. Zsebo, and K. Welte. "Effects of human stem cell factor (c-kit ligand) on proliferation of myeloid leukemia cells: heterogeneity in response and synergy with other hematopoietic growth factors." Blood 80, no. 5 (September 1, 1992): 1199–206. http://dx.doi.org/10.1182/blood.v80.5.1199.1199.
Анотація:
Abstract A novel hematopoietic growth factor, the stem cell factor (SCF), for primitive hematopoietic progenitor cells has recently been purified and its gene has been cloned. In this study we tested the mitogenic activity of recombinant human SCF on myeloid leukemia cells as well as the expression of its receptor. We have investigated the proliferation of 31 myeloid leukemia cell lines as well as fresh myeloid leukemic blasts from 17 patients in a 72-hour 3H-thymidine uptake assay in the presence of various concentrations of recombinant human (rh) SCF alone or in combination with saturating concentrations of granulocyte- macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, interleukin-3 (IL-3), or erythropoietin (EPO). Only five of 31 lines, but fresh leukemic blasts from 12 of 17 patients with acute myeloid leukemia (AML), significantly responded to SCF. The responding cell lines were of the acute promyelocytic, chronic myeloid, megakaryoblastic, and erythroleukemia origin, the responding blast preparations of all French-American-British subtypes. Synergistic activities of SCF were found with G-CSF, GM-CSF, EPO, and IL-3. To determine the SCF binding sites on leukemic cells, we used 125I- radiolabeled SCF in Scatchard analysis and cross-linking studies. The leukemic cell lines responding to SCF expressed from 2,300 up to 29,000 binding sites per cell. The SCF receptor expression was downregulated in vitro by the presence of its ligand. Cross-linking studies demonstrated a 150-Kd SCF receptor on the surface of all responding myeloid leukemias. This study suggests that SCF may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor for other cytokines. Furthermore, using polymerase chain reaction analysis of total RNA from the myeloid leukemia lines, we found expression of SCF-mRNA in 17 of 30 lines, suggesting autocrine mechanisms in the growth of a subgroup of leukemic cells by coexpression of SCF and its receptor.
15
Pietsch, T., U. Kyas, U. Steffens, E. Yakisan, MR Hadam, WD Ludwig, K. Zsebo, and K. Welte. "Effects of human stem cell factor (c-kit ligand) on proliferation of myeloid leukemia cells: heterogeneity in response and synergy with other hematopoietic growth factors." Blood 80, no. 5 (September 1, 1992): 1199–206. http://dx.doi.org/10.1182/blood.v80.5.1199.bloodjournal8051199.
Анотація:
A novel hematopoietic growth factor, the stem cell factor (SCF), for primitive hematopoietic progenitor cells has recently been purified and its gene has been cloned. In this study we tested the mitogenic activity of recombinant human SCF on myeloid leukemia cells as well as the expression of its receptor. We have investigated the proliferation of 31 myeloid leukemia cell lines as well as fresh myeloid leukemic blasts from 17 patients in a 72-hour 3H-thymidine uptake assay in the presence of various concentrations of recombinant human (rh) SCF alone or in combination with saturating concentrations of granulocyte- macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, interleukin-3 (IL-3), or erythropoietin (EPO). Only five of 31 lines, but fresh leukemic blasts from 12 of 17 patients with acute myeloid leukemia (AML), significantly responded to SCF. The responding cell lines were of the acute promyelocytic, chronic myeloid, megakaryoblastic, and erythroleukemia origin, the responding blast preparations of all French-American-British subtypes. Synergistic activities of SCF were found with G-CSF, GM-CSF, EPO, and IL-3. To determine the SCF binding sites on leukemic cells, we used 125I- radiolabeled SCF in Scatchard analysis and cross-linking studies. The leukemic cell lines responding to SCF expressed from 2,300 up to 29,000 binding sites per cell. The SCF receptor expression was downregulated in vitro by the presence of its ligand. Cross-linking studies demonstrated a 150-Kd SCF receptor on the surface of all responding myeloid leukemias. This study suggests that SCF may be an important factor for the growth of myeloid leukemia cells, either as a direct stimulus or as a synergistic factor for other cytokines. Furthermore, using polymerase chain reaction analysis of total RNA from the myeloid leukemia lines, we found expression of SCF-mRNA in 17 of 30 lines, suggesting autocrine mechanisms in the growth of a subgroup of leukemic cells by coexpression of SCF and its receptor.
16
Takimoto, Rishu, Junji Kato, Koichi Takada, Takuya Matsunaga, and Yoshiro Niitsu. "Impaired Expression of the DNA Repair Factor DDB2 in Human Myeloid Leukemias." Blood 104, no. 11 (November 16, 2004): 2046. http://dx.doi.org/10.1182/blood.v104.11.2046.2046.
Анотація:
Abstract Recent studies have suggested that chromosomal deletions might represent a mechanism of inactivation of DNA repair system in various hematological malignancies, including myeloid leukemias. However, the precise mechanisms remain unclear. Damaged DNA binding protein-2 (DDB2), a DNA repair factor induced by tumor suppressor p53, plays an important role in the nucleotide excision repair of UV-damaged DNA. Despite frequent mutations of p53 in human leukemic cells, the role of DDB2 on the leukemogenesis is unkown. In this study, we examined expression of DDB2 mRNA in four human myeloid leukemia cell lines (K562, KG1, HL60, and MEG01) and in fresh leukemic cells obtained from 4 patients with myeloid leukemias. In all leukemia cells, expression of DDB2 mRNA was remarkably decreased as compared to that of CD34 cells We then assayed DDB2-dependent DNA repairing activity in the leukemic cells using specific antibodies against photoproducts, and found that DNA repairing activity was reduced. When a plasmid encoding DDB2 gene (pCV-DDB2) was transduced into K562 cells, the DNA repairing activity was significantly restored. Finally we tested the expression of DDB2 mRNA in five myeloid leukemias obtained from patients, and found loss of DDB2 expression in four patients. These results suggested that in human myeloid leukemias, suppression of DDB2 expression may contribute to accumulation of gene mutation through the dysfunction of DNA repair.
17
Narayanan, Geetha, M. T. Sugeeth, and Lali V. Soman. "Mixed Phenotype Acute Leukemia Presenting as Leukemia Cutis." Case Reports in Medicine 2016 (2016): 1–3. http://dx.doi.org/10.1155/2016/1298375.
Анотація:
Leukemia cutis (LC) is defined as infiltration of the skin by leukemic cells resulting in clinically recognizable cutaneous lesions. It is common in congenital leukemia and acute myeloid leukemia. However, LC has rarely been reported with mixed phenotypic acute leukemia (MPAL). We report the case of a lady who presented with erythematous papular and nodular lesions all over the body. Skin biopsy showed leukemic infiltration and bone marrow aspiration showed MPAL of the T/myeloid with monocytic differentiation lineage. This is the first report of an adult patient with MPAL of the T/myeloid with monocytic differentiation type presenting with leukemia cutis. She was started on chemotherapy with Hyper-CVAD. There is complete resolution of the skin lesions and she has achieved bone marrow remission after the first cycle of chemotherapy.
18
Alten, Florian, Karoline Ehlert, Michael R. Böhm, and Ulrike H. Grenzebach. "Leukemic Hypopyon in Acute Myeloid Leukemia." European Journal of Ophthalmology 23, no. 2 (March 2013): 252–54. http://dx.doi.org/10.5301/ejo.5000177.
19
Shirazi, Nadia, Akriti Saxena, Kunal Das, and Vikas Shrivastava. "Small-Bowel Myeloid Sarcoma Presenting as A Relapse Case of Acute Myeloid Leukemia." Annals of Pathology and Laboratory Medicine 5, no. 7 (July 29, 2018): C107–110. http://dx.doi.org/10.21276/apalm.1876.
20
Dinndorf, PA, RG Andrews, D. Benjamin, D. Ridgway, L. Wolff, and ID Bernstein. "Expression of normal myeloid-associated antigens by acute leukemia cells." Blood 67, no. 4 (April 1, 1986): 1048–53. http://dx.doi.org/10.1182/blood.v67.4.1048.1048.
Анотація:
Abstract Monoclonal antibodies that react with hematopoietic cells and their precursors in a stage and lineage restricted fashion were used in indirect immunofluorescence assays to examine leukemic cells from 105 pediatric age patients. The differentiative states of blasts from 42 patients with acute nonlymphocytic leukemia (ANLL) were defined by these antibodies. When these were compared to their morphologic and histochemical levels of differentiation as defined by the French- American-British (FAB) classification, no direct relationship was found. The reactivity of these antibodies with leukemic cells from 63 patients with acute lymphocytic leukemiA (ALL) was also investigated, and the usefulness of these antibodies in distinguishing leukemias of myeloid from those of lymphoid origin was demonstrated.
21
Dinndorf, PA, RG Andrews, D. Benjamin, D. Ridgway, L. Wolff, and ID Bernstein. "Expression of normal myeloid-associated antigens by acute leukemia cells." Blood 67, no. 4 (April 1, 1986): 1048–53. http://dx.doi.org/10.1182/blood.v67.4.1048.bloodjournal6741048.
Анотація:
Monoclonal antibodies that react with hematopoietic cells and their precursors in a stage and lineage restricted fashion were used in indirect immunofluorescence assays to examine leukemic cells from 105 pediatric age patients. The differentiative states of blasts from 42 patients with acute nonlymphocytic leukemia (ANLL) were defined by these antibodies. When these were compared to their morphologic and histochemical levels of differentiation as defined by the French- American-British (FAB) classification, no direct relationship was found. The reactivity of these antibodies with leukemic cells from 63 patients with acute lymphocytic leukemiA (ALL) was also investigated, and the usefulness of these antibodies in distinguishing leukemias of myeloid from those of lymphoid origin was demonstrated.
22
Neog, Archana, Priyanka Singh, Sonu Kumar Gupta, and Malkhey Verma. "miRNA-An Alternative Therapy for Chronic Myeloid Leukemia." Asian Pacific Journal of Health Sciences 6, no. 1 (March 2019): 162–76. http://dx.doi.org/10.21276/apjhs.2019.6.1.24.
23
Pais, Anurita, Shailesh Pande, Gauri Pradhan, Akshay Tharali, Smita Patil, and Chaitali Parab. "Acute Myeloid Leukemia with complex hyperdiploidkaryotypeA Case Report." Annals of Pathology and Laboratory Medicine 2, no. 12 (December 17, 2018): C185–189. http://dx.doi.org/10.21276/apalm.2299.
24
Kurtzberg, J., TA Waldmann, MP Davey, SH Bigner, JO Moore, MS Hershfield, and BF Haynes. "CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells." Blood 73, no. 2 (February 1, 1989): 381–90. http://dx.doi.org/10.1182/blood.v73.2.381.381.
Анотація:
Abstract Following our initial observation of in vivo conversion of CD7+, CD4-, CD8- acute lymphoblastic leukemia (ALL) cells from lymphoid to myeloid lineages (Proc Natl Acad Sci (USA) 81:253, 1984) we have studied eight additional cases of ALL with this leukemic cell phenotype. The CD7+, CD4-, CD8- phenotype was associated with a distinct clinical entity with those affected predominantly male (either less than 35 years or greater than 65 years of age), with frequent mediastinal and/or thymic masses, skin and CNS disease, high peripheral WBC counts, and bone marrow blasts that were morphologically L1 or not ascribable to a specific lineage. These patients did not respond to conventional chemotherapeutic regimens for either acute lymphoid or myeloid leukemias. No common karyotype or T-cell gene rearrangement pattern could be defined. Importantly, seven of eight patient's leukemic cells studied were capable of multilineage (myeloid, erythroid, monocytoid, megakaryocytoid, and lymphoid) differentiation in vitro. Data is presented suggesting that CD7+, CD4-, CD8- leukemias, in many instances, are leukemias of immature hematopoietic cells. The development of novel therapeutic approaches to this form of leukemia will be necessary to alter its poor prognosis.
25
Kurtzberg, J., TA Waldmann, MP Davey, SH Bigner, JO Moore, MS Hershfield, and BF Haynes. "CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells." Blood 73, no. 2 (February 1, 1989): 381–90. http://dx.doi.org/10.1182/blood.v73.2.381.bloodjournal732381.
Анотація:
Following our initial observation of in vivo conversion of CD7+, CD4-, CD8- acute lymphoblastic leukemia (ALL) cells from lymphoid to myeloid lineages (Proc Natl Acad Sci (USA) 81:253, 1984) we have studied eight additional cases of ALL with this leukemic cell phenotype. The CD7+, CD4-, CD8- phenotype was associated with a distinct clinical entity with those affected predominantly male (either less than 35 years or greater than 65 years of age), with frequent mediastinal and/or thymic masses, skin and CNS disease, high peripheral WBC counts, and bone marrow blasts that were morphologically L1 or not ascribable to a specific lineage. These patients did not respond to conventional chemotherapeutic regimens for either acute lymphoid or myeloid leukemias. No common karyotype or T-cell gene rearrangement pattern could be defined. Importantly, seven of eight patient's leukemic cells studied were capable of multilineage (myeloid, erythroid, monocytoid, megakaryocytoid, and lymphoid) differentiation in vitro. Data is presented suggesting that CD7+, CD4-, CD8- leukemias, in many instances, are leukemias of immature hematopoietic cells. The development of novel therapeutic approaches to this form of leukemia will be necessary to alter its poor prognosis.
26
Parasole, Rosanna, Laura Vicari, Fara Petruzziello, Anna Leszl, Giuseppe Menna, M. Tarsitano, Luigi Del Vecchio, et al. "Trisomy of Chromosome 7: a Novel Cytogenetic Abnormality in a Paediatric Case of Mixed Acute Leukemia." Blood 114, no. 22 (November 20, 2009): 4121. http://dx.doi.org/10.1182/blood.v114.22.4121.4121.
Анотація:
Abstract Abstract 4121 Background Mixed acute leukemias are an heterogeneous category of poorly differentiated leukemias, affecting people of all ages. These forms of leukemias are very rare, 3-5% of all acute leukemias, and are characterized by co-expression of myeloid and lymphoid associated-antigens on the same leukemic cells. The therapeutic approach is not defined because, often, mixed leukemias switch their lineage of origin during treatment and the prognosis is very poor. We describe a novel, never reported before, cytogenetic abnormality in a child with a mixed acute leukemia. Methods On January 2009, a nonsyndromic 5 year-old boy was admitted at our Institution for an acute hyperleukocytosic leukemia (WBC > 100.000/L). The patient showed spleen enlargement and massive mediastinal lymphadenopathy. Morphological diagnosis of acute leukemia was based on the French-American-British criteria and the immunophenotypic diagnosis was performed by flow cytometry using a large panel of leukemia-associated antibodies (myeloid and B/T lymphoid markers). Cytogenetic analysis was performed on unstimulated overnight culture of bone marrow, followed by RHG-banding. The expression of T-cell receptor and rearrangement of heavy chain immunoglobulin was assessed by molecular methodology. Results Morphologic evaluation showed lymphoid blasts according to the FAB-L2 classification with same aberrations such as myeloid blebs and prominent nucleoli. The immunophenotype showed mixed expression of myeloid markers (MPO > 3%, CD33, CD11a, CD11b, CD117) and T lymphoid antigens (surface CD7, CD99 and cytoplasmic CD3) and an aberrant lineage-B expression (CD19). On the basis of these data the diagnosis of acute mixed leukemia was carried out. Cytogenetic analysis showed trisomy of chromosome 7, a chromosomal aberration never reported before in acute myeloid or lymphoid leukemia (figure 1). Ig or T-cell receptor gene rearrangements were not identified as well as translocations commonly found in either lymphoid and myeloid leukemias. The treatment was initially performed according to the acute lymphoblastic leukemia protocol (AIEOP ALL2000) but unresponsiveness as seen up to day +12 required a shift to a mixed personalized protocol with cyclophosphamide, dexamethasone and L-asparaginase associated with more specific drugs for myeloid lineage such as high dose cytarabine and etoposide. After a febrile aplasia, bone marrow reconstitution showed about 75% of mixed blasts. So the child shifted to a rescue protocol with fludarabine, cytarabine, idarubicine (FLA-Ida) repeated 2 times with a good haematological and cytometric response (0,9% of blasts). For consolidation of remission, was performed 1 cycle with clofarabine, cyclophosphamide and etoposide followed by 1 cycle with clofarabine and cytarabine with a minor response (1,9% of blasts by immunophenotype). Actually, the child is undergoing an unrelated mismatched transplant. Conclusion At the best of our knowledge, this case is the first report of trisomy 7 in a mixed acute leukemia in childhood. The only cytogenetic aberration known so far in pediatric mixed leukemias are: isochromosome 7, monosomy 7, or inversion 7 as well as translocations such as t(1;7), t(4;7) or t(7;15). Trisomy 7 is also described in some mesenchymal and neurogenic neoplasms such as brain, colon, ovary, prostate, bladder and kidney tumors and also in some non-neoplastic inflammatory disease such as rheumatoid arthritis and osteoarthritis. In haematological field, trisomy 7 is reported only in few cases of myeloma, non-Hodgkin lymphoma and amyloidosis. The prognostic significance of this cytogenetic aberration in mixed acute leukemias is still unknown. Disclosures: No relevant conflicts of interest to declare.
27
Oakley, Kevin, Yufen Han, Bandana A. Vishwakarma, Su Chu, Ravi Bhatia, Kristbjorn O. Gudmundsson, Jonathan Keller, et al. "Setbp1 promotes the self-renewal of murine myeloid progenitors via activation of Hoxa9 and Hoxa10." Blood 119, no. 25 (June 21, 2012): 6099–108. http://dx.doi.org/10.1182/blood-2011-10-388710.
Анотація:
Abstract Acquisition of self-renewal capability by myeloid progenitors to become leukemic stem cells during myeloid leukemia development is poorly understood. Here, we show that Setbp1 overexpression efficiently confers self-renewal capability to myeloid progenitors in vitro, causing their immortalization in the presence of stem cell factor and IL-3. Self-renewal after immortalization requires continuous Setbp1 expression. We also found that Hoxa9 and Hoxa10 mRNA are present at dramatically higher levels in Setbp1-immortalized cells compared with other immortalized cells, and are induced shortly after Setbp1 expression in primary myeloid progenitors. Suppression of either gene in Setbp1-immortalized cells drastically reduces their colony-forming capability. Interestingly, Setbp1 protein associates with Hoxa9 and Hoxa10 promoters in chromatin immunoprecipitation assays in these cells, suggesting that both are direct transcriptional targets of Setbp1. Setbp1 also promotes self-renewal of myeloid progenitors in vivo as its coexpression with BCR/ABL transforms primary mouse myeloid progenitors, generating aggressive leukemias in recipient mice resembling chronic myelogenous leukemia (CML) myeloid blast crisis. Increased SETBP1 mRNA levels were also detected in a subset of CML advanced phase/blast crisis patients with high levels of HOXA9 and HOXA10 expression. Thus, Setbp1 activation represents a novel mechanism conferring self-renewal capability to myeloid progenitors in myeloid leukemia development.
28
Adamaki, Maria, Spiros Vlahopoulos, George I. Lambrou, Athanasios G. Papavassiliou, and Maria Moschovi. "Aberrant AML1 gene expression in the diagnosis of childhood leukemias not characterized by AML1-involved cytogenetic abnormalities." Tumor Biology 39, no. 3 (March 2017): 101042831769430. http://dx.doi.org/10.1177/1010428317694308.
Анотація:
The AML1 ( acute myeloid leukemia 1) gene, a necessary prerequisite of embryonic hematopoiesis and a critical regulator of normal hematopoietic development, is one of the most frequently mutated genes in human leukemia, involving over 50 chromosome translocations and over 20 partner genes. In the few existing studies investigating AML1 gene expression in childhood leukemias, aberrant upregulation seems to specifically associate with AML1 translocations and amplifications. The aim of this study was to determine whether overexpression also extends to other leukemic subtypes than the ones karyotypically involving AML1. We use quantitative real-time polymerase chain reaction methodology to investigate gene expression in 100 children with acute leukemias and compare them to those of healthy controls. We show that in childhood acute lymphoblastic leukemia, AML1 gene overexpression is associated with a variety of leukemic subtypes, both immunophenotypically and cytogenetically. Statistically significantly higher transcripts of the gene were detected in the acute lymphoblastic leukemia group as compared to the acute myeloid leukemia group, where AML1 overexpression appeared to associate with cytogenetic abnormalities additional to those that engage the AML1 gene, or that are reported as showing a “normal” karyotype. Collectively, our study shows that AML1 gene overexpression characterizes a broader range of leukemic subtypes than previously thought, including various maturation stages of B-cell acute lymphoblastic leukemia and cytogenetic types additional to those involving the AML1 gene.
29
Abdel-Wahab, Omar, and Ross L. Levine. "Metabolism and the leukemic stem cell." Journal of Experimental Medicine 207, no. 4 (April 5, 2010): 677–80. http://dx.doi.org/10.1084/jem.20100523.
Анотація:
Acute leukemias are clonal disorders of hematopoiesis wherein a leukemic stem cell (LSC) acquires mutations that confer the capacity for unlimited self-renewal, impaired hematopoietic differentiation, and enhanced proliferation to the leukemic clone. Many recent advances in understanding the biology of leukemia have come from studies defining specific genetic and epigenetic abnormalities in leukemic cells. Three recent articles, however, further our understanding of leukemia biology by elucidating specific abnormalities in metabolic pathways in leukemic hematopoiesis. These studies potentially converge on the concept that modulation of reactive oxygen species (ROS) abundance may influence the pathogenesis and treatment of acute myeloid leukemia (AML).
30
Frankfurt, Olga, and Martin S. Tallman. "Growth Factors in Leukemia." Journal of the National Comprehensive Cancer Network 5, no. 2 (February 2007): 203–15. http://dx.doi.org/10.6004/jnccn.2007.0020.
Анотація:
The role of myeloid growth factors, such as granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, in the management of acute myeloid and acute lymphoblastic leukemias has been evaluated extensively in multiple clinical trials. Growth factors have been given before, concurrently, or sequentially with chemotherapy with the goal of reducing the duration of neutropenia and consequently the incidence and severity of infections, and improving the rate of remissions and overall survival. They also have been studied as chemotherapy-sensitizing agents in an effort to recruit dormant myeloid stem cells into the sensitive phase of the cycle. Additionally, growth factors, shown to stimulate proliferation and differentiation of leukemia cells in vitro, were evaluated as monotherapy in patients with acute leukemia. Most studies show modest improvement in the duration of the neutropenia, which does not consistently correlate with the severity of infection, rate or duration of remissions, or disease-free and overall survival. Attempts to enhance the chemosensitivity of the leukemic cells and decrease drug resistance failed to improve the rate of remission and survival in several large series. However, more recent reports suggested an improved outcome in younger patients with acute myeloid leukemia with normal karyotype. Several anecdotal case reports have shown that growth factor monotherapy can induce a complete remission in patients with acute leukemia. Data from the published clinical trials do not seem to support emergence of drug-resistant leukemia, worsening toxicity, and bone marrow failure with growth factor administration.
31
Shi, Yang, and Endi Wang. "Blastic Plasmacytoid Dendritic Cell Neoplasm: A Clinicopathologic Review." Archives of Pathology & Laboratory Medicine 138, no. 4 (April 1, 2014): 564–69. http://dx.doi.org/10.5858/arpa.2013-0101-rs.
Анотація:
Blastic plasmacytoid dendritic cell neoplasm is a rare entity grouped with the acute myeloid leukemia–related precursor neoplasms in the 2008 World Health Organization classification. It was previously postulated to originate from natural killer cells, T cells, or monocytes but is now believed to arise from the plasmacytoid dendritic cell. The pathogenesis of blastic plasmacytoid dendritic cell neoplasm is not well understood, although the neoplasm demonstrates frequent deletion of tumor suppressor genes, including RB1, CDKN1B, CDKN2A, and TP53. Blastic plasmacytoid dendritic cell neoplasm is a clinically aggressive tumor that often initially presents as cutaneous lesions and subsequently progresses to bone marrow involvement and leukemic dissemination. It is characterized by enhanced expression of CD56, CD4, and CD123, which can be detected by flow cytometry/immunohistochemistry. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and some mature T-cell lymphomas/leukemias. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplant may improve survival.
32
Pavlova, T. Yu, and T. T. Valiev. "Priapism as the first symptom of chronic myeloid leukemia: literature review and own clinical case report." Oncohematology 17, no. 4 (November 6, 2022): 88–93. http://dx.doi.org/10.17650/1818-8346-2022-17-4-88-93.
Анотація:
Chronic myeloid leukemia is a ph-positive myeloproliferative disease, which is usually manifested by hyperleukocytosis and massive splenomegaly. Chronic myeloid leukemia is rare in childhood and adolescence, it accounts for 2 to 3 % of all leukemias cases. priapism is a rare manifestation of chronic myeloid leukemia and is an urgent urological condition that requires timely treatment to prevent long-term complications, in particular, erectile dysfunction.This review presents the literature information about priapism as the first sign of chronic myeloid leukemia, as well as the first description in the Russian literature of a clinical case of priapism in a 9-year-old patient with chronic myeloid leukemia.
33
Jianbiao Zhou, Jessie Yiying Quah, Yvonne Ng, Jing-Yuan Chooi, Sabrina Hui-Min Toh, Baohong Lin, Tuan Zea Tan, et al. "ASLAN003, a potent dihydroorotate dehydrogenase inhibitor for differentiation of acute myeloid leukemia." Haematologica 105, no. 9 (November 7, 2019): 2286–97. http://dx.doi.org/10.3324/haematol.2019.230482.
Анотація:
Differentiation therapies achieve remarkable success in acute promyelocytic leukemia, a subtype of acute myeloid leukemia. However, excluding acute promyelocytic leukemia, clinical benefits of differentiation therapies are negligible in acute myeloid leukemia except for mutant isocitrate dehydrogenase 1/2. Dihydroorotate dehydrogenase catalyses the fourth step of the de novo pyrimidine synthesis pathway. ASLAN003 is a highly potent dihydroorotate dehydrogenase inhibitor that induces differentiation, as well as reduces cell proliferation and viability, of acute myeloid leukemia cell lines and primary acute myeloid leukemia blasts including in chemo-resistant cells. Apoptotic pathways are triggered by ASLAN003, and it also significantly inhibits protein synthesis and activates AP-1 transcription, contributing to its differentiation promoting capacity. Finally, ASLAN003 substantially reduces leukemic burden and prolongs survival in acute myeloid leukemia xenograft mice and acute myeloid leukemia patient-derived xenograft models. Notably, the drug has no evident effect on normal hematopoietic cells and exhibits excellent safety profiles in mice, even after a prolonged period of administration. Our results, therefore, suggest that ASLAN003 is an agent targeting dihydroorotate dehydrogenase with potential in the treatment of acute myeloid leukemia. ASLAN003 is currently being evaluated in phase 2a clinical trial in acute myeloid leukemia patients.
34
Noll, Judit, Dorottya Asbóth, Judit Csomor, Mónika Csóka, Gábor Kovács, Gergely Kriván, and Krisztián Kállay. "Newborn myeloid sarcoma." Bőrgyógyászati és Venerológiai Szemle 96, no. 5 (October 21, 2020): 257–60. http://dx.doi.org/10.7188/bvsz.2020.96.5.7.
Анотація:
Myeloid sarcoma according to the WHO 2016 version is an independent subgroup of acute myeloid leukemia, characterized by extramedullary tumor-like proliferation of myeloid precursor cells. Myeloid sarcoma can occur without bone marrow disease, associated with myeloid neoplasias or as a relapse of acute myeloid leukemia, too. In this article we describe the case of a 3 week-old newborn, whose myeloid sarcoma presented with skin symptoms and was successfully treated with AML BMF98 chemotherapy following allogeneic hematopoietic stem cell transplantation. Hereby we also summarize the most important current knowledges of the disease.
35
Xiao, Zhijian, Yushu Hao, and Shougeng Bian. "Acute myeloid leukemia M2B (subacute myeloid leukemia) in China." Leukemia Research 21, no. 4 (April 1997): 351–52. http://dx.doi.org/10.1016/s0145-2126(96)00101-4.
36
Horton, Sarah J., Vanessa Walf-Vorderwülbecke, Steve J. Chatters, Neil J. Sebire, Jasper de Boer, and Owen Williams. "Acute myeloid leukemia induced by MLL-ENL is cured by oncogene ablation despite acquisition of complex genetic abnormalities." Blood 113, no. 20 (May 14, 2009): 4922–29. http://dx.doi.org/10.1182/blood-2008-07-170480.
Анотація:
Abstract Chromosomal translocations involving 11q23 are frequent in infant acute leukemia and give rise to the formation of MLL fusion genes. The mechanism of leukemic transformation by these fusions has been the subject of numerous investigations. However, the dependence of acute leukemia on MLL fusion activity in vivo and the efficacy of targeting this activity to eliminate disease have not been established. We have developed a model for conditional expression of MLL-ENL in hematopoietic progenitor cells, in which expression of the fusion oncogene is turned off by doxycycline. Conditionally immortalized myeloblast cells derived from these progenitors were found to induce leukemia in vivo. Leukemic cells isolated from primary recipient mice were shown to have acquired additional genetic abnormalities and, when transplanted into secondary recipients, induced leukemia with shortened latencies. However, the leukemic cells remained dependent on MLL-ENL expression in vitro and in vivo, and its ablation resulted in regression of established leukemias. This study demonstrates that even genetically complex leukemias can be reversed on inactivation of the initiating MLL fusion and has important implications for the design of novel leukemia therapies.
37
Konopleva, Marina, Elena Elstner, Teresa J. McQueen, Twee Tsao, Andrey Sudarikov, Wei Hu, Wendy D. Schober та ін. "Peroxisome proliferator-activated receptor γ and retinoid X receptor ligands are potent inducers of differentiation and apoptosis in leukemias". Molecular Cancer Therapeutics 3, № 10 (1 жовтня 2004): 1249–62. http://dx.doi.org/10.1158/1535-7163.1249.3.10.
Анотація:
Abstract The peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor family that forms heterodimers with retinoid X receptor. These heterodimers bind to DNA and activate the transcription of target genes. Here, we report that the PPARγ receptor protein is expressed in primary myeloid and lymphoid leukemias and in lymphoma and myeloma cell lines. In this study, we compared the activity of several PPARγ ligands including BRL49653 (rosiglitazone), 15-deoxy-Δ12,14-prostaglandin J2, and the novel triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid on leukemia cells. Exposure to these PPARγ ligands induced apoptosis in myeloid (U937 and HL-60) and lymphoid (Su-DHL, Sup-M2, Ramos, Raji, Hodgkin's cell lines, and primary chronic lymphocytic leukemia) cells. A similar exposure to these PPARγ ligands induced the differentiation of myeloid leukemic cells. A combination of PPARγ ligands with a retinoid X receptor agonist (i.e., LG100268) or a retinoic acid receptor agonist (i.e., all trans-retinoic acid) enhanced differentiating and growth-inhibitory effects. 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced differentiation and apoptosis with much greater potency than the other PPARγ ligands in established cell lines and primary chronic lymphocytic leukemia samples. Exposure to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induced mitochondrial depolarization and caspase activation, which was associated with apoptosis induction. In Bcl-2-overexpressing chronic lymphocytic leukemia cells, the small-molecule Bcl-2 inhibitor HA14-1 sensitized these cells to 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid–induced apoptosis. These results suggest that PPARγ ligation alone and in combination with retinoids holds promise as novel therapy for leukemias by activating the transcriptional activity of target genes that control apoptosis and differentiation in leukemias.
38
Saeed, Zabila. "Extramedullary Acute Myeloid Leukemia: Testicular Myeloid Leukemia, Leukemia Cutis with Leptomeningeal Involvement." Blood 138, Supplement 1 (November 5, 2021): 4376. http://dx.doi.org/10.1182/blood-2021-146659.
Анотація:
Abstract Extramedullary Acute Myeloid Leukemia: Testicular myeloid leukemia, leukemia cutis with leptomeningeal involvement Z Saeed, H Aslam, A Weil, M Muzaffar Myeloid sarcoma also called granulocytic sarcoma, myeloblastoma, or chloroma is an extramedullary tumor of immature granulocytic cells. Extramedullary soft tissue manifestations are relatively rare in hematological malignancies. One of the rarest manifestations is myeloid sarcoma (MS). MS develops as part of acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome or at relapse, especially following allogeneic hematopoietic stem cell transplant. Demographically, it has a slight male predominance with a male to female ratio of 1.2: 1. It may occur at any age and any site in the body leading to varied clinical presentations. The most reported sites are lymph nodes, skin and soft tissues, bone, testes, gastrointestinal tract, and peritoneum. 44 year old male with past medical history of diabetes mellitus type 2 and morbid obesity presented with right testicular pain and swelling and underwent radical orchiectomy. Pathology reported seminoma and received adjuvant Carboplatin for pT3 disease. He developed left testicular pain and swelling 2 months later and underwent left radical orchiectomy. Pathology reported CD4+, CD56+ high grade hematopoietic neoplasm. It was sent for second opinion to NIH and was consistent with myeloid sarcoma with monoblastic features. Repeat evaluation of right testicular specimen was CD45+. Bone marrow biopsy showed normocellular marrow with multilineage hematopoiesis. PET scan showed hyper metabolic activity in the right hemi scrotum, widespread osseous areas of increased uptake and 3 soft tissue nodules within the subcutaneous tissues of the left abdominal wall. FNA of the subcutaneous nodule showed CD56 positive monocytoid cells. Induction chemotherapy with 7+3 (cytarabine 200 mg/m2, daunorubicin 60mg/m2) with gemtuzumab 3mg/m2 on day 1, 4, 7 was completed. Cerebrospinal fluid studies (CSF) showed monoblastic/monocytic proliferation and received intrathecal (IT) chemotherapy alternating between methotrexate and cytarabine every week. CSF studies were cleared after 2 IT chemotherapy. Patient remained in the hospital for 87 days due to poor count recovery and development of pulmonary embolism. Myeloid mutation screening identified a mutation in NRASG13D. Repeat PET scan showed 7 areas of hypermetabolic foci involving nodular densities of bilateral lower anterior abdominal wall. One of the lesion was biopsied that was negative. He completed 2 cycles of high dose cytarabine for consolidation but had repeated hospital admissions and therapy was switched to azacytidine and venetoclax. Patient was evaluated by bone marrow transplant team. He had disease progression at tenth month when he presented with severe back pain and lower extremity weakness. MRI brain and spine showed new patchy T2 hyperintense signal in the right frontal white matter, increased number and size of marrow replacing lesions throughout the visualized skeleton. Patient underwent bone biopsy that showed >90% marrow involvement (sheets of infiltrative cells with identical phenotype. Positive for CD56 (>90% of marrow cellularity), CD4 and lysozyme. Hospital course was complicated with renal failure, electrolytes imbalance and hemodynamically instability requiring vasopressor support. Discussions were held for re-induction with CLAG (cladribine 5mg/m2, and cytarabine 2gm/m2) vs best supportive care. Patient decided to pursue comfort care and passed away peacefully. The uniqueness of this case is the myeloid sarcoma of testes as initial presentation with normal bone marrow. Misdiagnosis is not uncommon and can delay the appropriate treatment. Extra medullary involvement from leukemia is very aggressive and needs high suspicious and prompt treatment. Systemic chemotherapy using AML-like regimens should be commenced early, even in non leukemic disease. Allogeneic hematopoietic stem cell transplantation has demonstrated promising results, particularly in patients who achieved complete remission with AML-induction protocols, and recent advances in genetic profiling may enable the development of novel targeted therapies. Prospective multicenter controlled trials are required to further refine management decisions and investigate the role of novel targeted therapies. Disclosures No relevant conflicts of interest to declare.
39
Kogan, Scott C., Suk-hyun Hong, David B. Shultz, Martin L. Privalsky та J. Michael Bishop. "Leukemia initiated by PMLRARα: the PML domain plays a critical role while retinoic acid–mediated transactivation is dispensable". Blood 95, № 5 (1 березня 2000): 1541–50. http://dx.doi.org/10.1182/blood.v95.5.1541.005k28_1541_1550.
Анотація:
The most common chromosomal translocation in acute promyelocytic leukemia (APL), t15;17(q22;q21), creates PMLRAR andRARPML fusion genes. We previously developed a mouse model of APL by expressing PMLRAR in murine myeloid cells. In order to examine the mechanisms by which PMLRAR can initiate leukemia, we have now generated transgenic mice expressingPMLRARm4 and RARm4, proteins that are unable to activate transcription in response to retinoic acid.PMLRARm4 transgenic mice developed myeloid leukemia, demonstrating that transcriptional activation by PMLRAR is not required for leukemic transformation. The characteristics of the leukemias arising in the PMLRARm4 transgenic mice varied from those previously observed in our PMLRAR transgenic mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARm4transgenic mice did not differentiate in response to retinoic acid therapy. This result supports the hypothesis that a major therapeutic effect of retinoic acid is mediated directly through thePMLRAR protein. However, a variable effect on survival suggested that this agent may be of some benefit in APL even when leukemic cells are resistant to its differentiative effects. Transgenic mice expressing high levels of RARm4 have not developed leukemia, providing evidence that the PML domain ofPMLRAR plays a specific and critical role in the pathogenesis of APL.
40
Smaldone, Giovanni, Luigi Coppola, Mariarosaria Incoronato, Rosanna Parasole, Mimmo Ripaldi, Luigi Vitagliano, Peppino Mirabelli, and Marco Salvatore. "KCTD15 Protein Expression in Peripheral Blood and Acute Myeloid Leukemia." Diagnostics 10, no. 6 (June 4, 2020): 371. http://dx.doi.org/10.3390/diagnostics10060371.
Анотація:
Leukocytes are major cellular components of the inflammatory and immune response systems. After their generation in the bone marrow from hematopoietic stem cells, they maturate as granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes. The abnormal accumulation and proliferation of immature blood cells (blasts) lead to severe and widespread diseases such as leukemia. We have recently shown that KCTD15, a member of the potassium channel tetramerization domain containing protein family (KCTD), is remarkably upregulated in leukemic B-cells. Here, we extend our investigation by monitoring the KCTD15 expression levels in circulating lymphocytes, monocytes, and granulocytes, as well as in leukemia cells. Significant differences in the expression level of KCTD15 were detected in normal lymphocytes, monocytes, and granulocytes. Interestingly, we also found overexpression of the protein following leukemic transformation in the case of myeloid cell lineage. Indeed, KCTD15 was found to be upregulated in K562 and NB4 cells, as well as in HL-60 cell lines. This in vitro finding was corroborated by the analysis of KCTD15 mRNA of acute myeloid leukemia (AML) patients reported in the Microarray Innovations in Leukemia (MILE) dataset. Collectively, the present data open interesting perspectives for understanding the maturation process of leukocytes and for the diagnosis/therapy of acute leukemias.
41
Dinndorf, PA, and GH Reaman. "Acute lymphoblastic leukemia in infants: evidence for B cell origin of disease by use of monoclonal antibody phenotyping." Blood 68, no. 4 (October 1, 1986): 975–78. http://dx.doi.org/10.1182/blood.v68.4.975.975.
Анотація:
Abstract Since the prognosis of infants with acute lymphoblastic leukemia (ALL) is so poor, it has been suggested that these leukemias may not be lymphoid in origin, but may originate from stem cell, myeloid, or megakaryocytic progenitors. Alternately it has been hypothesized that these leukemias originate in lymphoid cells at the earliest stages of B cell development. Another possibility is that these leukemias may be of more than one lineage. Therefore we examined leukemic blasts from 12 infants with ALL using monoclonal antibodies to myeloid and lymphoid differentiation antigens. The majority of specimens expressed HLA/DR and reacted with B4 (CD19) but failed to react with stem cell, myeloid, megakaryocytic, or T cell associated antibodies. These results support the speculation that the majority of these leukemias arise in cells at the earliest stages of B cell commitment, and are not of a myeloid or biphenotypic nature.
42
Dinndorf, PA, and GH Reaman. "Acute lymphoblastic leukemia in infants: evidence for B cell origin of disease by use of monoclonal antibody phenotyping." Blood 68, no. 4 (October 1, 1986): 975–78. http://dx.doi.org/10.1182/blood.v68.4.975.bloodjournal684975.
Анотація:
Since the prognosis of infants with acute lymphoblastic leukemia (ALL) is so poor, it has been suggested that these leukemias may not be lymphoid in origin, but may originate from stem cell, myeloid, or megakaryocytic progenitors. Alternately it has been hypothesized that these leukemias originate in lymphoid cells at the earliest stages of B cell development. Another possibility is that these leukemias may be of more than one lineage. Therefore we examined leukemic blasts from 12 infants with ALL using monoclonal antibodies to myeloid and lymphoid differentiation antigens. The majority of specimens expressed HLA/DR and reacted with B4 (CD19) but failed to react with stem cell, myeloid, megakaryocytic, or T cell associated antibodies. These results support the speculation that the majority of these leukemias arise in cells at the earliest stages of B cell commitment, and are not of a myeloid or biphenotypic nature.
43
Matulonis, UA, C. Dosiou, C. Lamont, GJ Freeman, P. Mauch, LM Nadler, and JD Griffin. "Role of B7-1 in mediating an immune response to myeloid leukemia cells." Blood 85, no. 9 (May 1, 1995): 2507–15. http://dx.doi.org/10.1182/blood.v85.9.2507.bloodjournal8592507.
Анотація:
A costimulatory signal from B7–1 (CD80) to its counter-receptor CD28 is required for T-cell activation. Many tumors, including most human leukemias, lack expression of B7–1, and this has been suggested to contribute to the failure of immune recognition of these diseases. A murine leukemia model system was developed to assess the potential role of B7–1 in the induction immunity to leukemia cells. The nonleukemic 32Dc13 myeloid cell line was transformed by transfection of the BCR/ABL gene, generating a subline (32Dp210/clone 26) that was leukemic and rapidly lethal to syngeneic, immunocompetent C3H/HeJ mice or T-cell-deficient nude mice. B7–1-modified leukemic cells remained lethal in nude mice, but caused only a transient, nonlethal leukemia in C3H/HeJ mice. After a single exposure to live, nonirradiated B7–1-modified leukemic cells, C3H/HeJ mice developed protective immunity against subsequent challenge with B7–1(-) leukemic cells. Further, hyperimmunization with B7–1(+) leukemic cells prolonged the survival of mice previously injected with a lethal number of B7–1(-) leukemic cells. These results indicate that myeloid leukemic cells may be attractive candidates for B7–1 gene transfer.
44
Saglio, Giuseppe, Anna Serra, Anna Novarino, Michele Falda, and Felice Gavosto. "N-Ras Mutations in Myeloid Leukemias." Tumori Journal 75, no. 4 (August 1989): 337–40. http://dx.doi.org/10.1177/030089168907500407.
Анотація:
The presence of mutations activating the N-ras gene was investigated by the polymerase chain reaction technique in twenty patients with acute myeloblastic leukemia (AML) at onset and in four patients with Ph' positive chronic myelogeneous leukemia (CML) either in chronic phase or in blast crisis. Four remission samples and four relapses from the AML cases were also studied. Mutations were found in five out of twenty (25%) untreated AML cases at onset. No mutations were detected in the complete remission samples, two of them with N-ras mutations during the leukemic phase. Two out of the four leukemia relapses were positive for the same N-ras mutation shown at presentation, whereas no new mutations were found in the other two initially negative cases. An N-ras mutation appeared during the blast crisis of one of the four CML, which were all negative during the chronic phase. In conclusion, whereas some data appear to be consistent with a role of the N-ras mutations as initiating events in myeloid leukemias, in other cases N-ras activation seems to represent a factor involved in progression. These data suggest that a partial overlapping between initiation and progression factors could exist in naturally occurring tumors.
45
Fishman, Hila, Shreyas Madiwale, Ifat Geron, Vase Bari, Wouter Van Loocke, Yael Kirschenbaum, Itamar Ganmore, et al. "ETV6-NCOA2 fusion induces T/myeloid mixed-phenotype leukemia through transformation of nonthymic hematopoietic progenitor cells." Blood 139, no. 3 (January 20, 2022): 399–412. http://dx.doi.org/10.1182/blood.2020010405.
Анотація:
Abstract Mixed-phenotype acute leukemia is a rare subtype of leukemia in which both myeloid and lymphoid markers are co-expressed on the same malignant cells. The pathogenesis is largely unknown, and the treatment is challenging. We previously reported the specific association of the recurrent t(8;12)(q13;p13) chromosomal translocation that creates the ETV6-NCOA2 fusion with T/myeloid leukemias. Here we report that ETV6-NCOA2 initiates T/myeloid leukemia in preclinical models; ectopic expression of ETV6-NCOA2 in mouse bone marrow hematopoietic progenitors induced T/myeloid lymphoma accompanied by spontaneous Notch1-activating mutations. Similarly, cotransduction of human cord blood CD34+ progenitors with ETV6-NCOA2 and a nontransforming NOTCH1 mutant induced T/myeloid leukemia in immunodeficient mice; the immunophenotype and gene expression pattern were similar to those of patient-derived ETV6-NCOA2 leukemias. Mechanistically, we show that ETV6-NCOA2 forms a transcriptional complex with ETV6 and the histone acetyltransferase p300, leading to derepression of ETV6 target genes. The expression of ETV6-NCOA2 in human and mouse nonthymic hematopoietic progenitor cells induces transcriptional dysregulation, which activates a lymphoid program while failing to repress the expression of myeloid genes such as CSF1 and MEF2C. The ETV6-NCOA2 induced arrest at an early immature T-cell developmental stage. The additional acquisition of activating NOTCH1 mutations transforms the early immature ETV6-NCOA2 cells into T/myeloid leukemias. Here, we describe the first preclinical model to depict the initiation of T/myeloid leukemia by a specific somatic genetic aberration.
46
Miner, Samantha, Sawa Ito, Kazushi Tanimoto, Nancy F. Hensel, Fariba Chinian, Keyvan Keyvanfar, Christopher S. Hourigan, et al. "Myeloid Leukemias Directly Suppress T Cell Proliferation Through STAT3 and Arginase Pathways." Blood 122, no. 21 (November 15, 2013): 3885. http://dx.doi.org/10.1182/blood.v122.21.3885.3885.
Анотація:
Abstract The immune-editing effect of myeloid leukemia has recently been reported in several studies. We previously demonstrated that the K562 leukemia-derived cell line suppresses T cell proliferation, which suggests that myeloid leukemia may function in a similar way to myeloid derived suppressor cells (MDSC). While the mechanism of suppression in leukemia is not fully understood, recent murine and human studies suggest that the STAT3 and arginase pathways play a key role in the immunosuppressive function of MDSC. We hypothesized that myeloid leukemia utilizes the MDSC STAT3 and arginase pathway to evade immune control, and block anti-leukemic immune responses. To evaluate the suppressive capacity of myeloid leukemia on T cell proliferation, we isolated CD34+ blasts and myeloid derived suppressor cells (MDSC: CD11b+CD14+) from blood of primary leukemia samples by FACS sorting (n=5). These cells were co-cultured with CFSE-labeled CD4+ T cells (n=9), previously isolated from healthy donor PBMCs using an automated cell separator (RoboSep). After stimulating with CD3/CD28 Dynabeads (Invitrogen, New York, USA) for 72 hours, proliferation was measured by CFSE dilution of the viable cell population. In three myeloid leukemias studied, CD4+ T cell proliferation was significantly suppressed in the presence of primary CD34 blasts and MDSC cells (p<0.001). Interestingly, CD34 blasts demonstrated a greater suppressive effect on T cells compared to MDSC cells for these samples (not statistically significant p=0.61). Next we repeated the proliferation assay using five leukemia cell lines: THP-1 and AML1 (derived from AML), K562 and CML1 (derived from CML), and the Daudi lymphoid-derived leukemia cell line. After staining with cell tracer dye and irradiating 100Gy, the cells were co-incubated with CFSE-labeled CD4+ T cells from healthy volunteers (n=6). We found that CD4+ T cell proliferation in the presence of the myeloid leukemia cell lines was significantly suppressed (mean proliferation 5.7±0.9% to 26.1±10.7%: p<0.0001 to 0.05) compared to lymphoid cell lines (mean proliferation 76.3±8.2%: p>0.05), consistent with the results obtained with the primary leukemia samples. To evaluate the impact of STAT3 and arginase on the immunosuppressive function of myeloid leukemia, the five cell lines were primed overnight with either arginase inhibitor (N(ω)-Hydroxy-nor-L-arginine; EMD Biosciences, Inc., California, USA) or two STAT3 inhibitors (STAT3 Inhibitor VI or Cucurbitacin I; EMD Millipore, Massachusetts, USA). Then, CD4+ T cells from healthy donors (n=3) were cultured with either (1) leukemia without any inhibitor (2) leukemia in the presence of inhibitor (3) leukemia primed with inhibitor. Priming leukemia with arginase inhibitor and STAT3 inhibitors almost completely abrogated their suppressive effect of T cell proliferation (p<0.001). We conclude that myeloid leukemia, like MDSC, directly immunosuppresses T cells, through STAT-3 and arginase. This finding may underlie the immune-editing of T cells by myeloid leukemia. Our results suggest that STAT3 inhibitors could be used to augment leukemia-targeted immunotherapy. Further investigation of T cell biology within the leukemia microenvironment is needed to further define immune editing mechanisms in myeloid leukemia. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures: No relevant conflicts of interest to declare.
47
Lee, Po-Shing, Ching-Nan Lin, Chientzu Liu, Chien-Tai Huang, and Wei-Shiou Hwang. "Acute Leukemia With Myeloid, B-, and Natural Killer Cell Differentiation." Archives of Pathology & Laboratory Medicine 127, no. 2 (February 1, 2003): e93-e95. http://dx.doi.org/10.5858/2003-127-e93-alwman.
Анотація:
Abstract Biphenotypic acute leukemias account for 4% to 8% of all acute leukemias. Most of these leukemias are of myeloid–B-cell or myeloid–T-cell lineage. Acute myeloid–natural killer cell leukemia has been recognized recently. We report the first case, to our knowledge, of CD56+ acute leukemia showing unequivocal myeloid and B-cell differentiation in a 20-year-old woman, whose blast cells were positive for myeloperoxidase, CD13, CD33, CD117, terminal deoxynucleotidyl transferase, CD19, CD20, CD22, CD34, HLA-DR, and CD56 but negative for CD3, CD5, CD7, and CD10. Rare Auer rods were identified in the blast cells. Polymerase chain reaction assays showed rearrangement of immunoglobulin heavy-chain gene and absence of Epstein-Barr virus DNA. We propose that this novel form of multilineage leukemia may represent the neoplastic counterpart of a progenitor that can give rise to myeloid, B, and natural killer cells.
48
Smith, Catherine C., and Neil P. Shah. "Mechanisms of Resistance to Targeted Therapies in Acute Myeloid Leukemia and Chronic Myeloid Leukemia." American Society of Clinical Oncology Educational Book, no. 32 (June 2012): 685–89. http://dx.doi.org/10.14694/edbook_am.2012.32.103.
Анотація:
Overview: Small molecule kinase inhibitors of BCR-ABL in chronic myeloid leukemia (CML) and of FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in acute myeloid leukemia (AML) have been successful at achieving remissions in these diseases as monotherapy, but these leukemias do not initially respond in a subset of patients (primary resistance) and they progress in an additional group of patients after an initial response (secondary resistance). Resistance to these agents can be divided into mechanisms that allow reactivation kinase activity and those that bypass reliance on oncogenic signaling mediated by the target kinase. Elucidation of clinical resistance mechanisms to targeted therapies for patients can provide important insights into disease pathogenesis and signaling.
49
Heuser, Michael, Geyongsin Park, Ping Xiang, Sarah Vollett, Malina Leung, Courteney Lai, Grace Lin, and R. Keith Humphries. "Microenvironment Determines Myeloid-Erythroid Lineage Switch in MN1 Leukemia." Blood 112, no. 11 (November 16, 2008): 2420. http://dx.doi.org/10.1182/blood.v112.11.2420.2420.
Анотація:
Abstract Transcriptional control of hematopoietic lineage fate relies on the integration of a multitude of intra- and extracellular signals. Interestingly, the leukemic phenotype of MLL-rearranged leukemias has recently been shown also to depend on signals from the microenvironment or secondary mutations. To test whether the microenvironement more generally impacts on leukemic phenotype and whether disruption of cytokine signaling could provide an antileukemic target, we exploited the MN1 model of AML under defined genetically modified microenvironmental conditions. Constitutive expression of MN1 in murine bone marrow rapidly induces myeloid leukemia accompanied by an early-onset severe anemia (Heuser et al. Blood 2007). Here we describe that FLT3 and c-kit signaling direct MN1 expressing cells towards the myeloid lineage whereas loss of both FLT3 and c-kit signaling directs MN1 expressing cells to an immature stage of the erythroid lineage. In addition we identify the N-terminus of MN1 as the critical domain that blocks terminal erythroid differentiation. Based on the finding that murine MN1-expressing bone marrow cell lines can be maintained in FLT3-ligand or low concentrations of stem cell factor (SCF) the requirement of both FLT3 and c-kit signaling for MN1 leukemias was investigated. Cells from FLT3-ligand −/− and c-kit mutated W41/W41 mice were used for transduction with MN1, and wildtype or FLT3-ligand −/− mice were used as recipients of MN1-transformed leukemic cells. Constitutive expression of MN1 in wildtype, FLT3-ligand −/−, or c-kit-deficient cells resulted in leukemic death after 30 to 50 days. Strikingly, constitutive expression of MN1 in W41/W41 cells and transplantation of these cells into FLT3-ligand −/− mice resulted in overt erythroleukemia, whereas expression of MN1 in W41/W41 or FLT3-ligand −/− and transplantation into wildtype recipients, or expression of MN1 in wildtype cells and transplantation into FLT3-ligand −/− cells resulted in myeloid leukemias. Quantitative gene expression analysis of genes associated with erythroid differentiation from leukemic bone marrow demonstrated that Gata-1, but not β-major globin or Klf-1 was significantly upregulated in the erythroleukemias compared to all other myeloid leukemias (p<.001), suggesting that erythroid differentiation was blocked at an early stage. A detailed structure-function analysis of MN1 was employed to identify the domain of MN1 required for the erythroid differentiation block. Deletion constructs of consecutive portions of 200 amino acids of MN1 were functionally characterized for their capacity to induce anemia and leukemia in mice and to block myeloid differentiation in vitro. Interestingly, deletion of the N-terminus of MN1 resulted in declining donor-derived WBC engraftment in mice but increasing donor-derived RBCs in peripheral blood up to 90% over the course of 16 weeks, whereas the other deletions did not show this pattern. Quantitative gene expression analysis of MN1-delN compared to full-length MN1 expressing cells from bone marrow four weeks after transplantation showed a significant increase of Gata-1, KLF-1, and b-major globin expression in MN1-delN expressing cells (p<.001). The ability to block myeloid differentiation was tested by coinfection of bone marrow cells with NUP98HOXD13 and either control vector, full-length MN1 or MN1-delN and determining the IC50 of ATRA. Whereas the IC50 for the control was 0.1 μM, it was >1000 fold higher for both full-length MN1 and MN1-delN, suggesting that the function of MN1 to block myeloid and erythroid differentiation is encoded in different domains of the protein. In summary, loss of FLT3-ligand and impairment of c-kit signaling convert MN1 leukemias from myeloid to erythroid phenotype, but do not change the course of the disease. In contrast, N-terminal deletion of MN1 abrogates the erythroid differentiation block and prevents leukemia, but retains the myeloid differentiation block. Thus, we demonstrate an important role of microenvironmental signals for lineage choice in leukemogenesis.
50
Walter, Roland B., Frederick R. Appelbaum, Elihu H. Estey, and Irwin D. Bernstein. "Acute myeloid leukemia stem cells and CD33-targeted immunotherapy." Blood 119, no. 26 (June 28, 2012): 6198–208. http://dx.doi.org/10.1182/blood-2011-11-325050.
Анотація:
Although the identification of cancer stem cells as therapeutic targets is now actively being pursued in many human malignancies, the leukemic stem cells in acute myeloid leukemia (AML) are a paradigm of such a strategy. Heterogeneity of these cells was suggested by clonal analyses indicating the existence of both leukemias resulting from transformed multipotent CD33− stem cells as well others arising from, or predominantly involving, committed CD33+ myeloid precursors. The latter leukemias, which may be associated with an intrinsically better prognosis, offer a particularly attractive target for stem cell-directed therapies. Targeting the CD33 differentiation antigen with gemtuzumab ozogamicin was the first attempt of such an approach. Emerging clinical data indicate that gemtuzumab ozogamicin is efficacious not only for acute promyelocytic leukemia but, in combination with conventional chemotherapy, also for other favorable- and intermediate-risk AMLs, providing the first proof-of-principle evidence for the validity of this strategy. Herein, we review studies on the nature of stem cells in AML, discuss clinical data on the effectiveness of CD33-directed therapy, and consider the mechanistic basis for success and failure in various AML subsets.