Academic literature on the topic 'Leukemia, cell signaling, therapeutic strategies'
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Journal articles on the topic "Leukemia, cell signaling, therapeutic strategies"
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Liang, Kai Ling, Loveena Rishi, and Karen Keeshan. "Tribbles in acute leukemia." Blood 121, no. 21 (May 23, 2013): 4265–70. http://dx.doi.org/10.1182/blood-2012-12-471300.
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Abstract There is growing research interest in the mammalian Tribbles (Trib) family of serine/threonine pseudokinases and their oncogenic association with acute leukemias. This review is to understand the role of Trib genes in hematopoietic malignancies and their potential as targets for novel therapeutic strategies in acute myeloid leukemia and acute lymphoblastic leukemia. We discuss the role of Tribs as central signaling mediators in different subtypes of acute leukemia and propose that inhibition of dysregulated Trib signaling may be therapeutically beneficial.
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Roti, Giovanni, Claudia Sorrentino, and Antonio Cuneo. "THERAPEUTIC TARGETING OF NOTCH SIGNALING PATHWAY IN HEMATOLOGICAL MALIGNANCIES." Mediterranean Journal of Hematology and Infectious Diseases 11, no. 1 (June 25, 2019): e2019037. http://dx.doi.org/10.4084/mjhid.2019.037.
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The Notch pathway plays a key role in several processes including stem-cell self-renewal, proliferation, and cell differentiation. Several studies identified recurrent mutations in hematological malignancies making Notch one of the most desirable target in leukemia and lymphoma. The Notch signaling mediates resistance to therapy and controls cancer stem cells supporting the development of on-target therapeutic strategies to improve patients’ outcome. In this brief review, we outline the therapeutic potential of targeting Notch pathway in T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia and mantle cell lymphoma.
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Liedtke, Michaela, and Michael L. Cleary. "Therapeutic targeting of MLL." Blood 113, no. 24 (June 11, 2009): 6061–68. http://dx.doi.org/10.1182/blood-2008-12-197061.
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AbstractTreatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.
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Reikvam, Håkon. "Inhibition of NF-κB Signaling Alters Acute Myelogenous Leukemia Cell Transcriptomics." Cells 9, no. 7 (July 12, 2020): 1677. http://dx.doi.org/10.3390/cells9071677.
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Acute myelogenous leukemia (AML) is an aggressive hematological malignancy. The pathophysiology of the disease depends on cytogenetic abnormalities, gene mutations, aberrant gene expressions, and altered epigenetic regulation. Although new pharmacological agents have emerged during the last years, the prognosis is still dismal and new therapeutic strategies are needed. The transcription factor nuclear factor-κB (NF-κB) is regarded a possible therapeutic target. In this study, we investigated the alterations in the global gene expression profile (GEP) in primary AML cells derived from 16 consecutive patients after exposure to the NF-κB inhibitor BMS-345541. We identified a profound and highly discriminative transcriptomic profile associated with NF-κB inhibition. Bioinformatical analyses identified cytokine/interleukin signaling, metabolic regulation, and nucleic acid binding/transcription among the major biological functions influenced by NF-κB inhibition. Furthermore, several key genes involved in leukemogenesis, among them RUNX1 and CEBPA, in addition to NFKB1 itself, were influenced by NF-κB inhibition. Finally, we identified a significant impact of NF-κB inhibition on the expression of genes included in a leukemic stem cell (LSC) signature, indicating possible targeting of LSCs. We conclude that NF-κB inhibition significantly altered the expression of genes central to the leukemic process.
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Tyner, Jeffrey W., Stephen Spurgeon, Luke B. Fletcher, Wayne Yang, Tibor Kovacsovics, Brian J. Druker, and Marc M. Loriaux. "A Small-Molecule Inhibitor Screen Rapidly Identifies Therapeutic Targets and Individualized Therapeutic Strategies In Patients with Acute and Chronic Leukemias." Blood 116, no. 21 (November 19, 2010): 2754. http://dx.doi.org/10.1182/blood.v116.21.2754.2754.
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Abstract Abstract 2754 The development of more effective and less toxic therapies for acute and chronic leukemias will require the identification of the molecular abnormalities contributing to leukemogenesis and the identification of drugs that specifically block the activity of these lesions. We hypothesize that aberrantly activated tyrosine kinase signaling pathways play a critical role in the pathogenesis of a substantial proportion of leukemia cases, and our preliminary data suggest that the molecular abnormalities causing aberrant kinase activation are unique in a significant number of patients. Thus, effective therapies for leukemia will need to be determined on an individual patient basis. To address this need, we have developed a function-first, small-molecule kinase inhibitor assay that can identify therapeutic targets in tyrosine kinase signaling pathways in primary leukemia samples and provide individualized therapeutic options in a clinically relevant time frame. Methods: To rapidly identify drug sensitivity profiles and activated kinase pathways in individual, primary leukemia samples, we have developed a small-molecule inhibitor array which includes 90 small-molecule, cell-permeable inhibitor compounds including a core of 36 tyrosine kinase inhibitors that collectively target the majority of the tyrosine kinome. Many of the inhibitors are available for clinical use or are in clinical development. Inhibitors were placed in 96-well plates at four serial dilutions to allow IC50 calculations. Three days after adding primary leukemia cells to each well, we performed a tetrazolium based cell viability assay to evaluate the effect of each inhibitor. Because most inhibitors affect multiple kinases, we utilized automated scripts to compare target specificities of compounds that uniquely decreased primary leukemia cell viability to identify potential targets. Results: In preliminary proof-of-principal experiments, we tested leukemia cell lines and primary leukemia samples with known activating tyrosine kinase mutations and Ba/F3 cell lines expressing activated tyrosine kinases. As expected, all cells showed hypersensitivity to compounds with activity against the primary, mutated target. In addition, downstream targets were frequently identified. For example, MKPL-1 cells, which depend on an activating CSF1R translocation for viability, also showed sensitivity to phosphoinositol 3-kinase and NFKB inhibitors. To date, we have fully analyzed approximately 150 primary myeloid and lymphoid leukemia samples. Hierarchical clustering of IC50 data for individual patients identifies activated pathways characteristic to specific leukemia subtypes. Pathways include PI3K activation in acute lymphoblastic leukemia, SRC kinase and BTK activation in chronic lymphocytic leukemia, FLT3 and KIT activation in AML patients, and MEK kinase activation in chronic myelomonocytic leukemia. Importantly, the results show heterogeneous inhibitor sensitivity profiles and potential kinase targets for individual samples even within diagnosis groups supporting a need for individualized targeted therapies. We are currently utilizing inhibitor assay results for clinical trial development. Approximately 40% of samples show sensitivity to at least one FDA approved drug in the inhibitor panel, and we are developing phase II proof-of-concept trials to test the ability of the inhibitor assay to predict effective targeted therapies for individual patients. Conclusions: Our data demonstrate that the small-molecule inhibitor functional assay can rapidly identify genes contributing to leukemogenesis, provide insights into their mechanism of action, and suggest therapeutic options. The unique patterns of inhibitor sensitivity in many samples support the hypothesis that tyrosine kinases and related pathways contributing to leukemogenesis in each patient may be different. These findings, in turn, support the concept that targeted therapy will be most effective when administered on an individualized basis. By utilizing our pre-clinical assay to select individualized leukemia therapies, we hope to create a platform upon which we can rapidly test the effectiveness of individualized kinase therapy and apply this information to enhance development of new drugs and new drug combinations in leukemia patients. Disclosures: Kovacsovics: Celator Pharmaceuticals: Research Funding. Druker:Molecular MD: Consultancy, Equity Ownership. Loriaux:Celator Pharmaceuticals: Research Funding.
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Hallek, Michael. "Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies." Blood 122, no. 23 (November 28, 2013): 3723–34. http://dx.doi.org/10.1182/blood-2013-05-498287.
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AbstractThe management of chronic lymphocytic leukemia (CLL) is undergoing profound changes. Several new drugs have been approved for CLL treatment (fludarabine, bendamustine, and the monoclonal antibodies alemtuzumab, rituximab, and ofatumumab) and many more drugs are in advanced clinical development to be approved for this disease. In addition, the extreme heterogeneity of the clinical course and our improved ability to foresee the prognosis of this leukemia by the use of clinical, biological, and genetic parameters now allow us to characterize patients with a very mild onset and course, an intermediate prognosis, or a very aggressive course with high-risk leukemia. Therefore, it becomes increasingly challenging to select the right treatment strategy for each condition. This article summarizes the currently available diagnostic and therapeutic tools and gives an integrated recommendation of how to manage CLL in 2013. Moreover, I propose a strategy how we might integrate the novel agents for CLL therapy into sequential treatment approaches in the near future.
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Thanendrarajan, S., Y. Kim, and I. G. H. Schmidt-Wolf. "Understanding and Targeting the Wnt/β-Catenin Signaling Pathway in Chronic Leukemia." Leukemia Research and Treatment 2011 (December 4, 2011): 1–7. http://dx.doi.org/10.4061/2011/329572.
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It has been revealed that the Wnt/β-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/β-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies.
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Stevenson, Freda K., Sergey Krysov, Andrew J. Davies, Andrew J. Steele, and Graham Packham. "B-cell receptor signaling in chronic lymphocytic leukemia." Blood 118, no. 16 (October 20, 2011): 4313–20. http://dx.doi.org/10.1182/blood-2011-06-338855.
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Abstract The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach.
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Bremer, Edwin, Bram ten Cate, Douwe F. Samplonius, Lou F. M. H. de Leij, and Wijnand Helfrich. "CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia." Blood 107, no. 7 (April 1, 2006): 2863–70. http://dx.doi.org/10.1182/blood-2005-07-2929.
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AbstractAgonistic anti-Fas antibodies and multimeric recombinant Fas ligand (FasL) preparations show high tumoricidal activity against leukemic cells, but are unsuitable for clinical application due to unacceptable systemic toxicity. Consequently, new antileukemia strategies based on Fas activation have to meet the criterion of strictly localized action at the tumor-cell surface. Recent insight into the FasL/Fas system has revealed that soluble homotrimeric FasL (sFasL) is in fact nontoxic to normal cells, but also lacks tumoricidal activity. We report on a novel fusion protein, designated scFvCD7:sFasL, that is designed to have leukemia-restricted activity. ScFvCD7:sFasL consists of sFasL genetically linked to a high-affinity single-chain fragment of variable regions (scFv) antibody fragment specific for the T-cell leukemia-associated antigen CD7. Soluble homotrimeric scFvCD7:sFasL is inactive and acquires tumoricidal activity only after specific binding to tumor cell-surface-expressed CD7. Treatment of T-cell acute lymphoblastic leukemia (T-ALL) cell lines and patient-derived T-ALL, peripheral T-cell lymphoma (PTCL), and CD7-positive acute myeloid leukemia (AML) cells with homotrimeric scFvCD7:sFasL revealed potent CD7-restricted induction of apoptosis that was augmented by conventional drugs, farnesyl transferase inhibitor L-744832, and the proteasome inhibitor bortezomib (Velcade; Millenium, Cambridge, MA). Importantly, identical treatment did not affect normal human peripheral-blood lymphocytes (PBLs) and endothelial cells, with only moderate apoptosis in interleukin-2 (IL-2)/CD3-activated T cells. CD7-restricted activation of Fas in T-cell leukemic cells by scFvCD7:sFasL revitalizes interest in the applicability of Fas signaling in leukemia therapy.
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Rodriguez-Rodriguez, Sonia, Lin Wang, Huajia Zhang, Amy Zollman, Angelo A. Cardoso, and Nadia Carlesso. "SKP2 Is Dispensable for Normal T-Cell Development but Required for T-Cell Leukemogenesis." Blood 124, no. 21 (December 6, 2014): 2214. http://dx.doi.org/10.1182/blood.v124.21.2214.2214.
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Abstract Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer. Despite the significant clinical successes in the treatment of pediatric T-ALL, leukemia relapse, refractory disease and induction failure (around 30% of patients) remain significant clinical problems, which are often life-threatening. ALL remains the second leading cause of childhood death. Thus, more effective, curative therapeutic strategies are much needed, particularly for refractory and relapse T- ALL. Recent advances in understanding the biology and the molecular alterations of acute lymphoblastic leukemias have led to identification of new molecular targets, such as the Notch signaling pathway. Constitutive activation of Notch signaling is involved in more than 50% of human T-ALL, and overexpression of activated Notch induces T-cell leukemia and lymphoma in murine tumor models. However, disruption of Notch signaling by gamma-secretase inhibitors (GSI) failed to fulfill its clinical promise and, overall, the significant advances attained in dissecting the molecular effectors in T-ALL has yet to translate into effective, curative molecular therapies for relapse patients. Furthermore, despite multiple studies on Notch signaling, little is known on the role of its downstream mediators in T-cell ALL. Previous studies in our laboratory demonstrated that Notch1 activation induces transcriptional activation of SKP2, the F-box protein of the SCF E3-ubiquitin ligase complex. SKP2 is the main F-box protein regulating cell cycle, promoting downregulation of the CKIs (p21Cip1, p27Kip1, p57Kip2 and p130) and its overexpression accelerate cell cycle progression in hematopoietic cells. SKP2 overexpression is frequently associated with cancers, in particular lymphomas and leukemias, and correlates with poor prognosis. We found that Skp2 expression is dynamically regulated during T-cell development coinciding with the Notch expression pattern. Moreover, primary thymocytes cultured in vitro, responded to Notch stimulation by the Delta1 ligand increasing their Skp2 expression and their cell cycle status, whereas the loss of SKP2 impaired their ability to mount a proliferative response to IL-7 stimulation. Importantly, we observed that SKP2 expression is increased in T-ALL patient samples and that mice with Notch-induced T-cell leukemia showed 5 fold upregulation of Skp2 expression. Our hypotheses are that Notch activation promotes T-cell leukemogenesis by altering the cell cycle control through upregulation of Skp2, and that selective targeting of SKP2 is a novel, effective therapeutic strategy for childhood T-ALL. To test whether SKP2 is a key downstream mediator of Notch in T-ALL, we transduced oncogenic Notch (ICN; the constitutive intracellular form) in hematopoietic cells lacking SKP2 from Skp2-/- null mice, and in controls and we determine their ability to induce leukemia in irradiated recipients. Loss of SKP2 significantly delayed the development of T-cell leukemia and increased animal survival by 40%. Taken together, these results demonstrate a previously unrecognized role for SKP2 in the initiation and progression of T-ALL and its potential role as a therapeutic target. Disclosures No relevant conflicts of interest to declare.
Dissertations / Theses on the topic "Leukemia, cell signaling, therapeutic strategies"
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SARNO, JOLANDA. "Cell signaling in high risk childhood B cell precursor acute lymphoblastic leukemia: high-throughput dissection and targeting strategies." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2016. http://hdl.handle.net/10281/116109.
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Acute lymphoblastic leukemia is the most common childhood tumor and about 85% of cases are due to the expansion of a clone of B-cell precursors (BCP-ALL). Steady progress in development of effective treatments has led to an elevated rate of success in treating this disease. To date, even thought about 75% of patients are cured, 25% of cases having a relapse has a survival probability of only 30%.
Of note, more than 50% of relapses concern patients not classified in high-risk groups based on assessment of prognostic factors at diagnosis or on measurement of Minimal Residual Disease (MRD), a surrogate parameter of individual response to therapy.
The understanding of the molecular pathogenesis of the disease and the biological basis for explaining different clinical response represent the most relevant challenges in the field that could open new perspectives in the identification of either new prognostic factors or new molecules for targeted therapeutic approaches. In this setting we focused our studies on a poor prognosis subtype of BCP-ALL, bearing rearrangements in the Cytokine Receptor Like Factor 2 (CRLF2) gene. Alterations in the CRLF2 gene (CRLF2r) are present in about 10% of childhood BCP-ALL, 50% of Down Syndrome ALL and 50% of Ph-like ALL and are responsible of the overexpression of Thymic Stromal Lymphopoietin Receptor (TSLPR).We first studied the phenotypic expression of TSLPR and its associated molecular and phosphosignaling profile in a large and prospective cohort of patients, demonstrating that the TSLPR screening at diagnosis can be successfully performed by standardized flow cytometry protocols. We further found an activation of both JAK/STAT and PI3K/mTOR pathways in the CRLF2 rearranged patients giving the rationale to test targeted tyrosine kinase inhibitors (TKIs) to treat this subgroup of patients. Starting from these evidences we investigate the TSLPR-driven pathway by using a new high dimensional single cell approach, called mass cytometry (CyTOF), that allow the simultaneous measurement of about 50 parameters per cell. By applying this technology we studied 15 BCP-ALL (9 CRLF2r and 6 CRLF2wt) primary samples treating the cells with 3 different TKIs (Dasatinib, Ruxolitinib and BEZ235) and 2 anti-TSLPR monoclonal antibodies. We demonstrated a strong signaling inhibition with Dasatinib, Ruxolitinib and one anti-TSLPR mAb in CRLF2r BCP-ALL samples associated with a synergic in vitro efficacy of JAK/STAT inhibitors (Ruxolitinib and anti-TSLPR mAb) with Dasatinib and BEZ235 in BaF3 CRLF2/IL7Rα expressing cells. We also studied the MRD cells at Day 8 and Day 15 showing that the MRD cells of CRLF2r patients maintain their TSLPR positivity and responsiveness to both stimulation and drug treatment. Meanwhile, we also tested a histone deacetylase inhibitor, Givinostat, as a new therapeutic tool to use with conventional chemotherapy for childhood CRLF2r BCP-ALL. We demonstrated an in vitro inhibition and cell death induction of BCP-ALL CRLF2r cell lines at very low doses confirmed by a cytotoxic effect also in ex-vivo experiments where Givinostat was able to kill blast cells preserving the normal hematopoietic counterpart as demonstrated by a CyTOF analysis. In vivo Givinostat was able to markedly reduce the engraftment of leukemic blasts in the bone marrow of treated mice causing a transcriptional modulation of genes involved in JAK/STAT pathway leading to the inactivation of the signaling network. In the last part of our project we studied, in collaboration with Dr.Kara Davis at Stanford University, 60 primary diagnostic samples with known outcome in order to investigate possible features correlated with relapse. By using CyTOF we identified 8 predictors that separate patients who will relapse from whose who will not and these features suggested a high basal activation of IL-7 signaling node in late pro-B cells and poor response following pre-BCR engagement in pre-BI cells in patients going to relapse.
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Kokhaei, Parviz. "Preclinical therapeutic vaccination strategies in malignancies with focus on B-cell chronic lymphocytic leukemia /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-595-X/.
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Kawata, Takahito. "Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising therapeutic target for Adult T-cell Leukemia." Kyoto University, 2018. http://hdl.handle.net/2433/232109.
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Barata, João Taborda. "Interleukin-7 - mediated signaling and its role in the biology of T-cell acute lymphoblastic leukemia : potential targets for therapeutic intervention." Doctoral thesis, Porto : Edição do Autor, 2002. http://hdl.handle.net/10216/64645.
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Barata, João Taborda. "Interleukin-7 - mediated signaling and its role in the biology of T-cell acute lymphoblastic leukemia : potential targets for therapeutic intervention." Tese, Porto : Edição do Autor, 2002. http://catalogo.up.pt/F?func=find-b&local_base=UPB01&find_code=SYS&request=000090476.
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Fabiani, C. "SPHINGOLIPID SIGNALING AS A TARGET IN PHOTORECEPTOR DEGENERATION: AN IN VITRO MODEL FOR THERAPEUTIC STRATEGIES IN RETINITIS PIGMENTOSA." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/237138.
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Introduzione: gli Sfingolipidi sono una vasta famiglia di molecole con il duplice ruolo di componenti strutturali di membrane e mediatori intra ed extra cellulari. Sono implicati nel controllo di proliferazione, differenziazione e sopravvivenza cellulare ma anche di fenomeni legati alla morte, tra cui l’apoptosi. Ceramide (Cer), alla base degli sfingolipidi complessi, può andare incontro a deacilazione generando sfingosina e sfingosina-1-fosfato (S1P). Quest’ultimo è considerato un mediatore di sopravvivenza e proliferazione cellulare, in opposizione a Cer, che promuove arresto del ciclo ed apoptosi. La degenerazione retinica ed, in particolare la Retinite Pigmentosa (RP) sono associate all’accumulo di Cer ed all’induzione di morte cellulare. L’inibizione della sintesi e dell’accumulo di Cer, inattivando la serina palmitoiltransferasi (SPT) attraverso l’utilizzo di Miriocina, è stata dimostrata essere coinvolta nel recupero morfologico e funzionale dei fotorecettori retinici, in particolare dei coni, in un modello murino di RP (mutante rd10).
Scopo: Il nostro scopo è di intervenire sul metabolismo degli sfingolipidi per ridurre il danno di fotorecettori retinici, attarveso l’utilizzo di una linea cellulare di fotorecettori coni. In particolare, promuovendo l’aumento di S1P intracellulare, tramite l’inibizione dell’enzima S1P liasi, e la riduzione di Cer attraverso l’inattivazione di SPT.
Metodi: le cellule murine 661W, una linea di fotorecettori (coni), sono state trattate con 2-acetil-4(5)-(1(R),2(S),3(R),4-tetraidrobutil)-imidazolo (THI) 75µM, un inibitore dell’enzima S1Pliasi, per 2 ore; quindi, le cellule sono state sottoposte a deprivazione di siero e trattate con H2O2 1mM per differenti lassi di tempo. La curva di crescita di queste cellule è stata determinata attraverso il saggio MTT e la vitalità con Typan blue. Il saggio TUNEL e il FRAP test sono stati impiegati per verificare, rispettivamente, il grado di apoptosi e il potere antiossidante intrinseco dei fotorecettori. I contenuti intracellulari di sfingolipidi sono stati misurati attraverso l’analisi LC-MS. La tecnica del Western blotting, attraverso l’impiego di anticorpi specifici, è stata utilizzata per valutare la fosforilazione di ERK1/2 e Akt/PKB, il rapporto tra Bcl-2/Bax e l’espressione proteica di Nrf2. Attraverso Real time-PCR, le modulazioni nell’espressione dei trascritti di HO-1 e dei recettori di S1P sono stati valutati in seguito a stress ossidativo e trattamento con THI. S1P esogeno (100nM) e Miriocina (10µM) sono stati impiegati, rispettivamente 1 ora e 5 ore prima H2O2, per antagonizzare l’effetto dello stimolo ossidativo sui fotorecettori. In fine, abbiamo esaminato 30 composti di nuova sintesi per determinare la loro capacità inibitoria su SPT, attraverso un saggio di attività enzimatica.
Risultati: i nostri risultati mostrano che l’aumentata stabilità di S1P, ottenuta tramite l’utilizzo di THI, è in grado di ridurre l’effetto inibitorio sulla proliferazione e la vitalità cellulare, dato dalla deprivazione di siero e dal trattamento con H2O2. Il pretrattamento con THI, infatti, antagonizza la de-fosforilazione di ERK1/2 e la fosforilazione di Akt su Ser473, indotte dagli stimoli di morte utilizzati. Abbiamo, quindi, focalizzato la nostra ricerca sugli effetti dello stress ossidativo, evidenziando che THI si contrappone all’induzione dell’apopstosi tramite l’aumento del rapporto Bcl-2/Bax e influenza il potere antiossidante intrinseco dei fotorecettori modulando la via di segnale di Nrf2 e HO-1. Inoltre, THI aumenta l’espressione dei recettori di S1P, mostrando un effetto maggiore sui recettori S1P4 e S1P5. Inoltre, abbiamo osservato che basse concentrazioni di S1P migliorano la proliferazione, la vitalità e la risposta antiossidante di cellule 661W, mentre alte concentrazioni portano alla saturazione dei recettori.Il pretrattamento con miriocina, sia da solo che in combinazione con THI, protegge i fororecettori dallo stress ossidativo e riduce drasticamente i livelli intracellulari di tutte le specie di Cer. Parallelamente, abbiamo selezionato tre composti con attività inbitoria su SPT, determinando i rispettivi valori di IC50 che sono risultati essere compresi tra 17,71µM e 40,41µM.
Conclusioni: possiamo quindi concludere che la stabilizzazione di S1P e, più in generale, l’azione sul metabolismo degli sfingolipidi è da considerarsi un target terapeutico per promuovere la sopravvivenza fotorecettoriale in differenti condizioni di stress, tra cui lo stress ossidativo.Background: Sphingolipids are a broad class of molecules with the double role of cell membranes components and intra/extra cellular signal mediators, controlling proliferation, differentiation, stress survival and apoptosis. Ceramide (Cer), the core of complex sphingolipids, can undergo deacylation giving rise to sphingosine and sphingosine-1-phosphate (S1P). This latter exerts a pro-survival and proliferative activity, as opposed to Cer, which promotes cell cycle arrest and apoptosis. Retinal degeneration and in particular Retinitis Pigmentosa (RP) are associated to Cer accumulation and cell death induction. In a murine model of RP (rd10 mutant mice), it has been demonstrated that inhibition of Cer synthesis and accumulation, blocking serine palmitoyltransferase (SPT) with Myriocin, rescues retinal photoreceptors, especially cones, from degeneration. Aim: Our aim is to target sphingolipid metabolism to reduce retinal photoreceptor damage, in a cone photoreceptors cell line. In particular, promoting S1P intracellular increase by S1Plyase inhibition and Cer depletion through SPT inactivation. Methods: Murine 661W cone-like cell line were treated with 75µM 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI), an inhibitor of S1Plyase, for 2 hours; next, cells were starved and treated with 1mM H2O2 for different times. Cell growth curve was determined by MTT assay and viability with Trypan blue. TUNEL assay and FRAP test were employed to verify, respectively, apoptosis degree and antioxidant-intrinsic power. Sphingolipid intracellular amounts were measured through LC-MS analysis. ERK1/2 and Akt/PKB phosphorylation, Bcl-2/Bax ratio and Nrf2 expression was evaluated by Western blotting with specific antibodies. Real time-PCR was performed to establish HO-1 and S1P receptors transcript changes upon THI and oxidative stress treatments. Exogenous S1P (100nM) and Myriocin (10µM) were also employed, respectively 1 hour and 5 hours before H2O2, to antagonize oxidative stress effect on photoreceptors. Lastly, we screened 30 new synthetic compounds to determine their ability in inhibiting SPT, through an enzymatic activity assay. Results: We show that enhanced stability of S1P, obtained through THI administration, reduces inhibitory starvation and H2O2 effect on cell proliferation and viability. In particular, through THI ability to reverse stresses-induced ERK1/2 dephosphorylation and Akt phosphorylation on Ser473. We focused our investigations on oxidative stress, finding that THI counteracts H2O2-induced apoptosis increasing Bcl-2/Bax ratio and antioxidant-intrinsic power modulating Nrf2/HO-1 pathway. Furthermore, THI differentially induces S1P receptors transcript expression, showing the major effect on S1P4 and S1P5. In addition, low exogenous S1P improves 661W proliferation, viability and antioxidant response, whereas higher concentration leads to S1P receptors saturation. Myriocin treatment, either alone or in combination with THI, rescues photoreceptors from H2O2-induced oxidative stress and drastically reduces all Cer pools. Simultaneously, we selected three compounds with inhibitory activity on SPT, showing an IC50 values ranging from 17.71µM to 40.41µM. Conclusions: We conclude that S1P stabilization and, in general, sphingolipid metabolism manipulation can be considered a therapeutic target in order to promote photoreceptors survival under different stress conditions, such as oxidative stress.
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Lonetti, Annalisa <1982>. "Study of PI3K/Akt signaling pathway as potential molecular target for T-cell acute lymphoblastic leukemia (T-ALL) treatment: pan-inhibition of PI3K catalitic isoforms as better therapeutic approach." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6763/1/Annalisa_Lonetti_tesi.pdf.
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Class I phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric lipid kinases consisting of a regulatory subunit and one of four catalytic subunits (p110α, p110β, p110γ or p110δ). p110γ/p110δ PI3Ks are highly enriched in leukocytes. In general, PI3Ks regulate a variety of cellular processes including cell proliferation, survival and metabolism, by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Their activity is tightly regulated by the phosphatase and tensin homolog (PTEN) lipid phosphatase. PI3Ks are widely implicated in human cancers, and in particular are upregulated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to loss of PTEN function. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. At present different compounds which target single or multiple PI3K isoforms have entered clinical trials. In the present research, it has been analyzed the therapeutic potential of the pan-PI3K inhibitor BKM120, an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T-lymphoblasts. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. BKM120 efficacy was confirmed in in vivo studies to a subcutaneous xenotransplant model of human T-ALL. Because it is still unclear which agents among isoform-specific or pan inhibitors can achieve the greater efficacy, further analyses have been conducted to investigate the effects of PI3K inhibition, in order to elucidate the mechanisms responsible for the proliferative impairment of T-ALL.
Overall, these results indicated that BKM120 may be an efficient treatment for T-ALLs that have aberrant up-regulation of the PI3K signaling pathway and strongly support clinical application of pan-class I PI3K rather than single-isoform inhibitors in T-ALL treatment.
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Lonetti, Annalisa <1982>. "Study of PI3K/Akt signaling pathway as potential molecular target for T-cell acute lymphoblastic leukemia (T-ALL) treatment: pan-inhibition of PI3K catalitic isoforms as better therapeutic approach." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6763/.
Full textAbstract:
Class I phosphatidylinositol 3-kinases (PI3Ks) are heterodimeric lipid kinases consisting of a regulatory subunit and one of four catalytic subunits (p110α, p110β, p110γ or p110δ). p110γ/p110δ PI3Ks are highly enriched in leukocytes. In general, PI3Ks regulate a variety of cellular processes including cell proliferation, survival and metabolism, by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). Their activity is tightly regulated by the phosphatase and tensin homolog (PTEN) lipid phosphatase. PI3Ks are widely implicated in human cancers, and in particular are upregulated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to loss of PTEN function. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. At present different compounds which target single or multiple PI3K isoforms have entered clinical trials. In the present research, it has been analyzed the therapeutic potential of the pan-PI3K inhibitor BKM120, an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T-lymphoblasts. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. BKM120 efficacy was confirmed in in vivo studies to a subcutaneous xenotransplant model of human T-ALL. Because it is still unclear which agents among isoform-specific or pan inhibitors can achieve the greater efficacy, further analyses have been conducted to investigate the effects of PI3K inhibition, in order to elucidate the mechanisms responsible for the proliferative impairment of T-ALL.
Overall, these results indicated that BKM120 may be an efficient treatment for T-ALLs that have aberrant up-regulation of the PI3K signaling pathway and strongly support clinical application of pan-class I PI3K rather than single-isoform inhibitors in T-ALL treatment.
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Varin, Elodie. "Identification de nouvelles stratégies thérapeutiques renforçant le rôle des analogues du GLP-1 pour préserver et/ou restaurer la masse fonctionnelle β pancréatique." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T015.
Full textAbstract:
Les cellules β pancréatiques synthétisent et sécrètent l'insuline, seule hormone hypoglycémiante de l'organisme. Dans le cas du diabète de type 2, du diabète de type 1 et suite à une greffe d'îlots de Langherans, on observe une diminution drastique de cette masse fonctionnelle β. L'hyperglycémie chronique et la libération de cytokines proinflammatoires jouent un rôle cytotoxique prépondérant dans ces phénomènes. Dans le but de préserver ou de restaurer cette masse fonctionnelle β chez les patients diabétiques, notre objectif était d'identifier des outils permettant de protéger des effets délétères de l'hyperglycémie chronique et des cytokines proinflammatoires, en s'intéressant à 3 cibles potentielles. Nous montrons tout d'abord que les activités du système ubiquitine protéasome (UPS), impliqué dans la dégradation de protéines, sont altérées en condition d'hyperglycémie chronique. Ces altérations sont corrélées à l'émergence d'un programme apoptotique au sein des cellules β. L'activation du récepteur du GLP-1 (Glucagon-Like Peptide-1), stratégie thérapeutique majeure dans le diabète de type 2, protège l'UPS des effets délétères de l'hyperglycémie chronique. Le facteur de transcription CREB (cAMP Response Element Binding Protein), essentiel pour la survie et la fonction des cellules β, est dégradé par l'hyperglycémie chronique et l'inflammation. Nous montrons que la prévention de sa dégradation prévient les effets de l'hyperglycémie chronique, mais pas de l'inflammation. Ces observations nous ont amenés à étudier la MAP3 kinase Tpl2 (Tumor progression locus 2), impliquée, notamment via l'activation de ERK1/2 (Extra-cellular Regulated Kinases 1/2), dans les processus inflammatoires d'autres types cellulaires. Nous montrons que Tpl2 est exprimé dans la lignée cellulaire β INS-1E, et dans les îlots murins et humains, et qu'elle gouverne spécifiquement l'activation des kinases ERK1/2 induite par les cytokines proinflammatoires IL-1β, TNFα et IFNγ. Cette protéine est surexprimée dans des conditions d'inflammation (in vitro et modèle de diabète murin). L'inhibition de Tpl2 protège contre l'apoptose induite par les cytokines, dans les INS-1E et les îlots de souris et restaure la capacité sécrétrice d'insuline des ilots de souris altérée suite à une exposition aux cytokines. En combinaison avec un analogue du GLP-1, l'inhibition pharmacologique de cette kinase protège totalement contre les effets délétères des cytokines sur la fonction et la survie des îlots humains. Ces données suggèrent que l'inhibition pharmacologique de la kinase Tpl2, seule ou en combinaison avec un analogue du GLP-1, pourrait constituer de nouvelles stratégies thérapeutiques pour protéger contre l'altération de la masse fonctionnelle β pouvant survenir chez des patients diabétiques de type 2 ou après la transplantation d'îlotsPancreatic β cells synthesize and secrete insulin, the sole hormone of the organism able to reduce glycemia. In the course of type 2 and type 1 diabetes, and after islet transplantation, there is a drastic loss of function and mass of these cells. Among the common origins of this decrease, chronic hyperglycemia and the release of proinflammatory cytokines play major roles. With the aim to preserve or to restore this functional β cell mass in diabetic patients, our objective was to identify tools able to protect against deleterious effects of these two phenomenons, interesting in three potential targets. We first demonstrated that the ubiquitin-proteasome system (UPS) activities, that degrade proteins, are altered in β cells exposed to chronic hyperglycemia, and correlated with apoptosis. Activation of the GLP-1 (Glucagon-Like Peptide-1) receptor, a key therapeutic strategy in type 2 diabetes, protects UPS from deleterious effects of chronic hyperglycemia. The transcription factor CREB (cAMP Response Element Binding Protein), crucial for β cell survival and function, is involved in deleterious effects of chronic hyperglycemia and inflammation. We demonstrated that prevention of CREB degradation protects β cells from chronic hyperglycemia, but not from the deleterious effects of the proinflammatory cytokines. These observations prompted us to study the MAP3 kinase Tpl2 (Tumor progression locus 2), known to be implicated in inflammatory process in other cell types, through the activation of the kinases ERK1/2 (Extra-cellular Regulated Kinases 1/2). We showed that Tpl2 is expressed in INS-1E clonal β cells and in mouse and human islets, and that it governs specifically the activation of ERK1/2 in response to proinflammatory cytokines IL-1β, TNFα and IFNγ. This protein is overexpressed by inflammatory conditions and in a rat type 2 diabetes model. Inhibition of Tpl2 protects against cytokine-induced apoptosis in INS-1E and in mouse islets. Furthermore, the capacity of mouse islets to secrete insulin in response to glucose, that is altered by a chronic exposure to cytokines, is restored by Tpl2 inhibitor. Finally, we showed that in combination with GLP-1 analog (Exendin-4), Tpl2 inhibitor can entirely restore the survival and function in human islets cultured in pro-inflammatory conditions. These results suggest that pharmacological inhibition of Tpl2, alone or in combination with Exendin-4, may be novel therapeutic strategies to alleviate β-cell failure observed in Type 2 diabetes and islets transplantation
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"The effect of arsenic trioxide on acute megakaryocytic leukemia : signaling, cell cycle arrest, and apoptosis." 2004. http://library.cuhk.edu.hk/record=b5892202.
Full textAbstract:
Lam Kin Bong Hubert.Thesis (M.Phil.)--Chinese University of Hong Kong, 2004.
Includes bibliographical references (leaves 139-161).
Abstracts in English and Chinese.
Abstract (in English) --- p.i
(in chinese) --- p.iv
Acknowledgements --- p.vi
Publications --- p.ix
Table of Contents --- p.x
List of Tables --- p.xiii
List of Figures --- p.xiv
List of Abbreviations --- p.xvi
Chapter CHAPTER1： --- General Introduction --- p.1
Chapter Section 1.1 --- Historical Background and Application of Arsenic Trioxide as an Anti-cancer Agent --- p.1
Chapter Section 1.2 --- Arsenic Trioxide Induces Apoptosis in Cancer Cells --- p.3
Chapter 1.2.1 --- The Intrinsic and Extrinsic Pathways of Apoptosis Initiation --- p.4
Chapter 1.2.2 --- The Convergence of Pathways --- p.8
Chapter 1.2.3 --- Induction of Apoptosis by Arsenic Trioxide --- p.9
Chapter 1.2.3.1 --- Controversies in the Involvement of the Extrinsic Pathway --- p.9
Chapter 1.2.3.2 --- "Arsenic Trioxide, Oxidative Stress and the Mitochondria" --- p.10
Chapter 1.2.3.3 --- Caspase-3 Activation in Arsenic Trioxide-mediated Apoptosis --- p.12
Chapter Section 1.3 --- Arsenic Trioxide Perturbs the Cell Division Cycle --- p.13
Chapter 1.3.1 --- The Cell Cycle Oscillator --- p.14
Chapter 1.3.2 --- DNADamage and Cell Cycle Checkpoints --- p.15
Chapter 1.3.3 --- Induction of Cell Cycle Arrest by Arsenic Trioxide and its Association with Apoptosis --- p.17
Chapter Section 1.4 --- Acute Megakaryocytic Leukemia and Arsenic Trioxide --- p.20
Chapter CHAPTER 2： --- Objectives --- p.28
Chapter CHAPTER 3： --- Methodology --- p.30
Chapter Section 3.1 --- Materials --- p.30
Chapter Section 3.2 --- Methods --- p.39
Chapter 3.2.1 --- Culture of Megakaryocytic Cells and Their Treatment with Arsenic Trioxide --- p.39
Chapter 3.2.1.1 --- Maintenance of Cell Lines --- p.39
Chapter 3.2.1.2 --- Treatment with Arsenic Trioxide --- p.39
Chapter 3.2.2 --- "Effects of Arsenic Trioxide on Cell Proliferation, Apoptosis, Mitochondrial Integrity and Cell Division Cycle Profiles of Human Megakaryocytic Leukemia Cell Lines" --- p.40
Chapter 3.2.2.1 --- Trypan Blue Exclusion Assay --- p.40
Chapter 3.2.2.2 --- Quantitation of Externalized Phosphatidylserine --- p.41
Chapter 3.2.2.3 --- Quantitation of Active Caspase-3 Expression --- p.42
Chapter 3.2.2.4 --- Assessment of Mitochondrial Intensity --- p.42
Chapter 3.2.2.5 --- Analysis of Cell Division Cycle Profile --- p.43
Chapter 3.2.2.6 --- Analysis of Cell Cycle Kinetics by BrdU Labeling --- p.43
Chapter 3.2.2.7 --- Identification of Cell Cycle Specificity of Caspase-3 Expression --- p.45
Chapter 3.2.3 --- Effects of Arsenic Trioxide on the Expression of Apoptotic Signals in Human Megakaryocytic Leukemia Cell Lines --- p.45
Chapter 3.2.3.1 --- Effects of Arsenic Trioxide on mRNA Expression Levels of Apoptotic Regulators --- p.45
Chapter 3.2.3.2 --- Effects of Arsenic Trioxide on Protein Expression Levels of Apoptotic Regulators --- p.50
Chapter 3.2.3.2.1 --- Flow Cytometric Analysis --- p.50
Chapter 3.2.3.2.2 --- Western Blot Analysis --- p.51
Chapter 3.2.4 --- Effects of Arsenic Trioxide on Gene Expression Profiles of Human Megakaryocytic Leukemia Cell Lines By Microarray Analysis --- p.54
Chapter 3.2.5 --- Statistical Analysis --- p.57
Chapter CHAPTER 4： --- "Effects of Arsenic Trioxide on Cell Proliferation, Apoptosis, Mitochondrial Integrity and Cell Division Cycle Profiles of Human Megakaryocytic Leukemia Cell Lines" --- p.62
Chapter Section 4.1 --- Introduction --- p.62
Chapter Section 4.2 --- Results --- p.63
Chapter 4.2.1 --- Effects of Arsenic Trioxide on Proliferation Kinetics --- p.63
Chapter 4.2.2 --- Effects of Arsenic Trioxide on Cell Viability --- p.64
Chapter 4.2.3 --- Apoptosis-inducing Capability of Arsenic Trioxide --- p.65
Chapter 4.2.3.1 --- Quantitation of Externalized Phosphatidylserine --- p.65
Chapter 4.2.3.2 --- Quantitation of Active Caspase-3 Expression --- p.66
Chapter 4.2.4 --- Effects of Arsenic Trioxide on Mitochondrial Integrity --- p.67
Chapter 4.2.5 --- Effects of Arsenic Trioxide on Cell Division Cycle Profiles --- p.69
Chapter 4.2.6 --- Effects of Arsenic Trioxide on Cell Cycle Kinetics by Bromodeoxyuridine Labeling --- p.69
Chapter 4.2.7 --- Identification of Cell Cycle Specificity of Arsenic Trioxide-Induced Caspase-3 Activation --- p.71
Chapter Section 4.3 --- Discussion --- p.72
Chapter CHAPTER 5： --- Effects of Arsenic Trioxide on Apoptotic Signal Expression in Human Megakaryocytic Leukemia Cell Lines --- p.91
Chapter Section 5.1 --- Introduction --- p.91
Chapter Section 5.2 --- Results --- p.92
Chapter 5.2.1 --- Effects of Arsenic Trioxide on mRNA Expression Levels of Apoptotic Regulators --- p.92
Chapter 5.2.2 --- Effects of Arsenic Trioxide on Protein Expression Levels of Apoptotic Regulators --- p.94
Chapter 5.2.2.1 --- Flow Cytometric Analysis --- p.94
Chapter 5.2.2.2 --- Western Blot Analysis --- p.96
Chapter Section 5.3 --- Discussion --- p.96
Chapter CHAPTER 6： --- Effects of Arsenic Trioxide on Gene Expression Profiles of Human Megakaryocytic Leukemia Cell Lines by Microarray Analysis --- p.119
Chapter Section 6.1 --- Introduction --- p.119
Chapter Section 6.2 --- Results --- p.119
Chapter Section 6.3 --- Discussion --- p.122
Chapter CHAPTER 7： --- General Discussion and Conclusions --- p.135
BIblography --- p.139
Book chapters on the topic "Leukemia, cell signaling, therapeutic strategies"
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Piazza, Francesco, and Gianpietro Semenzato. "Signalling Molecules as Selective Targets for Therapeutic Strategies in Multiple Myeloma." In Cell Signaling & Molecular Targets in Cancer, 87–108. New York, NY: Springer New York, 2011. http://dx.doi.org/10.1007/978-1-4614-0730-0_5.
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Podszywalow-Bartnicka, Paulina, Magdalena Wolczyk, and Katarzyna Piwocka. "Targeting of Post-Transcriptional Regulation as Treatment Strategy in Acute Leukemia." In Acute Leukemias [Working Title]. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.94421.
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Post-transcriptional regulation is an important step of gene expression that allows to fine-tune the cellular protein profile (so called proteome) according to the current demands. That mechanism has been developed to aid survival under stress conditions, however it occurs to be hijacked by cancer cells. Adjustment of the protein profile remodels signaling in cancer cells to adapt to therapeutic treatment, thereby enabling persistence despite unfavorable environment or accumulating mutations. The proteome is shaped at the post-transcriptional level by numerous mechanisms such as alternative splicing, mRNA modifications and triage by RNA binding proteins, change of ribosome composition or signaling, which altogether regulate the translation process. This chapter is an overview of the translation disturbances found in leukemia and their role in development of the disease, with special focus on the possible therapeutic strategies tested in acute leukemia which target elements of those regulatory mechanisms.
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Benbouchta, Yahya, Ahmed Afailal Tribak, and Khalid Sadki. "Research of the Philadelphia Chromosome in Chronic Myeloid Leukemia: Diagnostic and Prognostic Interests." In Cytogenetics - Classical and Molecular Strategies for Analysing Heredity Material. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.95865.
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Myeloproliferative syndromes are cell proliferation involving one or more medullary lines without blocking maturation. Chronic myeloid leukemia (CML) is the most common of these syndromes, it corresponds to the monoclonal proliferation of a multipotent stem cell; the myeloblastic or lymphoblastic transformation of CM. has a poor prognosis. The Philadelphia chromosome t(9;22)(q34;q11) is the first cytogenetic abnormality that has been associated with a malignant process. It is found in 89 to 95% of CML. The search for the Philadelphia chromosome (Ph1) has multiple interests: Diagnostic, prognostic and in therapeutic monitoring. The search for the Philadelphia chromosome by molecular cytogenetics makes it possible to remedy the poverty of cell suspensions in metaphase to take up the inconclusive results of classic cytogenetics on nuclei in interphase and to detect residual disease during therapeutic monitoring. Through the literature review, we highlight the importance of the identification of the Philadelphia chromosome in Myeloproliferative Syndromes for the improvement of the quality healthcare of the affected patients.
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Becerra, Edgardo, Valeria Soto-Ontiveros, and Guadalupe García Alcocer. "CRISPR-Cas9-based Strategies for Acute Lymphoblastic Leukemia Therapy." In Leukemia - From Biology to Diagnosis and Treatment [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.106702.
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Defeating cancer as leukemia has been an up and down challenge. However, leukemia must be treated from the roots. Nowadays, the CRISPR-Cas9 system provided scientists the ability to manipulate the genetic information to correct mutations, rewrite genetic code, or edit immune cells for immunotherapy purposes. Additionally, such system is used for basic and clinical approaches in leukemia therapy. Lymphoid cancers including acute lymphoblastic leukemia (ALL) can be treated by performing gene editing or enhancing immune system through CART cells. Here, we present and detail therapeutic applications of the CRISPR/Cas9 system for immune cell therapy, and knock-out or knock-in of main genes promoting leukemogenesis or ALL progression. We also described current and future challenges, and optimization for the application of CRISPR/Cas9 system to treat lymphoid malignancies.
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Becerra Becerra, Edgardo, and Guadalupe García-Alcocer. "MicroRNAs and Their Role in Acute Lymphoblastic Leukemia." In Acute Leukemias [Working Title]. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.94960.
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Acute lymphoblastic leukemia (ALL) has been established as the most common acute leukemia in children, accounting for 80–85% of cases. ALL occurs mostly in children and it is considered as a high-risk disease in the elderlies. ALL is characterized by a clonal disorder where the normal hematopoiesis is replaced by a malignant clonal expansion of lymphoid progenitors. Although many therapeutic strategies have been established to treat ALL leading to improved survival rates, the short-term and long-term complications derived from treatment toxicity represent a critical risk for patients. The treatment-related toxicity suggests a need for the development of new therapy strategies to effectively treat high-risk and low-risk disease. Nowadays, an important approach is focused on the identification of molecules involved in the mechanisms that lead to leukemia generation and progression to determine potential targets at the transcriptional level. MicroRNAs (miRNAs) are a group of key molecules that regulate signaling pathways related to lymphopoiesis. miRNAs participate in the regulation of hematopoietic differentiation and proliferation, as well as their activity. The present review details the recompilation of evidences about the relation between miRNAs and lymphopoiesis, ALL development and progression in order to propose and explore novel strategies to modulate ALL-related miRNA levels as a therapeutic approach.
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Leotta, Salvatore, Annalisa Condorelli, Giovanni Schininà, Roberta Sciortino, Alessandra Cupri, and Giuseppe Milone. "Stem Cell Transplantation in Acute Myeloid Laeukemia." In Acute Leukemias. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.94416.
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Allogeneic hematopoietic stem cell transplantation represents the only potentially curative therapeutic approach for Acute Myeloid Leukemia. The choice to perform an allogeneic hematopoietic transplant is the result of a decision-making process that considers disease-related factors (AML-risk category and the state of disease at the time of transplant), the type of donor available and his characteristics (HLA compatibility, gender, CMV serostatus) and the individual risk associated with the procedure itself. The choice of the appropriate conditioning regimen depends on the patient’s age and comorbidities. While the introduction of reduced intensity regimen and the availability of alternative donors allows more patients to be eligible for transplantation, myeloablative conditioning remains the standard of care for fit patients. Disease relapse is the leading cause of treatment failure and new strategies attempting at reducing the relapse incidence post transplantation are currently being investigated.
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Moruzzi, Noah, and Francesca Lazzeri-Barcelo. "Insulin Receptor Isoforms in Physiology and Metabolic Disease." In Insulin Resistance - Evolving Concepts and Treatment Strategies [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.103036.
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Insulin receptors (IRs) are ubiquitously expressed and essential for all cell types. Their signaling cascades are connected to key pathways involved in cell metabolism, proliferation, and differentiation, amongst others. Thus, dysregulation of IR-mediated signaling can lead to diseases such as metabolic disorders. In mammals, the IR pre-mRNA is alternatively spliced to generate two receptor isoforms, IR-A and IR-B, which differ in 12 amino acids in the α-chain involved in ligand binding. Given the isoforms have different affinities for their ligands insulin, proinsulin, and insulin-like growth factors (IGFs), it is speculated that IR amount and splicing regulation might contribute to a change in IR-mediated effects and/or insulin resistance. The aim of this chapter is to increase awareness of this subject in the research fields of diseases characterized by disturbances in insulin signaling. Here, we will describe the IR isoform distribution and discuss the current knowledge of their expression and ligand binding affinities as well as their signaling in physiology and during obesity and type 2 diabetes in humans and animal models. Moreover, we will discuss the necessary steps to gain a better understanding on the function and regulation of the IR isoforms, which could result in future therapeutic approaches against IR-related dysfunction.
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Srivastava, Ruby. "Role of Activated Cdc42-Associated Kinase 1 (ACK1/TNK2)-Inhibitors in Precision Oncology." In Drug Repurposing - Molecular Aspects and Therapeutic Applications [Working Title]. IntechOpen, 2022. http://dx.doi.org/10.5772/intechopen.102343.
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Activated Cdc42-associated kinase 1 (ACK1) is an intracellular non-receptor tyrosine kinase referred to as TNK2, which is considered as an oncogene and therapeutic target in various cancers including breast cancer, non-small-cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), and many others. Oncogenic non-receptor tyrosine kinase mutations occur either due to point mutations, duplications or insertions and deletions, or by involving in the development of a fusion gene resulting from a chromosomal rearrangement. ACK1 is involved with multiple signaling pathways of tumor progression. With these signaling networks, ACK1 participates in cell survival, invasion, migration, and tumorigenesis that are strongly related to the prognosis and clinicopathology of cancers. Previous studies predicted that ACK1 is a carcinogenic factor and blockage of ACK1 inhibits cancer cell survival, proliferation, migration, and radiation resistance. FDA has approved many multi-kinase inhibitors as therapeutic drugs that show good inhibitory activity not against ACK1 but also towards multiple targets. As ACK1 is a key target for other neurological diseases, inflammation, and immunological diseases also, so the studies on these inhibitors not only provide potential strategies for the treatment of cancers that require simultaneous targeting of multiple targets but also can be used in drug repurposing for other diseases.
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Jain, Sapna, and Manjari Singh. "Engineering of Extracellular Vesicles as Nano Therapy for Breast Cancer." In Physiology. IntechOpen, 2021. http://dx.doi.org/10.5772/intechopen.101149.
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Extracellular vesicles are membrane-derived nanoparticles that represent a novel mechanism of cell-to-cell communication. It is well reported that EVs play a central role in the tumor microenvironment by mediating intercellular signaling among cancer cells. This has resulted in the development of therapeutic strategies targeting various EV signaling pathways in cancer. However, because of their small size and endogenous origin, they have been extensively explored for cancer drug delivery. Hence, owing to their natural ability to mediate intercellular communication, high stability, and low immunogenicity, they have emerged as an attractive platform for cancer treatment. However, limited production and insufficient loading with therapeutic moieties are some of the issues constraining their clinical translation. In this chapter, recent research studies performed in an attempt to develop EVs as cancer biomarkers or drug delivery systems will be discussed. Further, it will also discuss various strategies such as direct and indirect cell surface modification, which can be employed to make EVs successful as cancer therapeutics. Furthermore, it will highlight the current and completed clinical trials using naturally derived EVs as cancer therapeutics.
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Panovska-Stavridis, Irina. "Molecular Monitoring in Acute Myeloid Leukemia Patients Undergoing Matched Unrelated Donor: Hematopoietic Stem Cell Transplantation." In Acute Leukemias [Working Title]. IntechOpen, 2020. http://dx.doi.org/10.5772/intechopen.94830.
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Minimal residual disease (MRD) in acute myeloid leukemia (AML) is a complex, multi-modality assessment and much as its clinical implications at different points are extensively studied, it remains even now a challenging area. It is the disease biology that governs the modality of MRD assessment; in patients harboring specific molecular targets, high sensitivity techniques can be applied. In AML patients undergoing allogenic hematopoietic stem cell transplantation (alloHSCT), relapse in considered as leading cause for treatment failure. In post-transplant setting, regular MRD status assessment enables to identify patients at risk of impending relapse when early therapeutic intervention may be beneficent. We analyzed data of AML patients who underwent matched unrelated donor (MUD) HSCT since the introduction of this procedure in the Republic of North Macedonia. Chimeric fusion transcripts were identified in three patients; two of them positive for RUNX-RUNX1T1 transcript and one for CBFB-MYH11. One patient harbored mutation in the transcription factor CCAAT/enhancer binding protein α (CEBPA). Post-transplant MRD kinetics was measured by quantitative polymerase chain or multiplex fluorescent-PCR every three months after the transplantation during the first two years after the transplant. MRD negativity was achieved in three patients by the sixth month of HSCT, who were pre-transplant MRD positive. They sustained hematological and molecular remission for 19, 9 and 7 months, respectively. The forth patient died due to transplant-related complication. Our experience suggests, when molecularly-defined AML patients undergo HSCT, regular MRD monitoring helps predict impending relapse and direct future treatment strategies.
Conference papers on the topic "Leukemia, cell signaling, therapeutic strategies"
1
Herzog, Lee-or, Bianca J. Lee, Thanh-Trang Vo, Honyin Chiu, Sharmila Mallya, Amos Fung, Mallika Singh, et al. "Abstract IA17: Strategies to target the mTORC1/eIF4F axis in B-cell leukemia and lymphoma." In Abstracts: AACR Special Conference on Targeting PI3K/mTOR Signaling; November 30-December 8, 2018; Boston, MA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1557-3125.pi3k-mtor18-ia17.
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Kuttikrishnan, Shilpa, Kirti S. Prabhu, Tamam Elimat, Ashraf Khalil, Nicholas H. Oberlies, Feras Q. Alali, and Shahab Uddin. "Anticancer Activity of Neosetophomone B, An Aquatic Fungal Secondary Metabolite, Against Hematological Malignancie S." In Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0106.
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Cancer is one of the most life threatening diseases, causing nearly 13% death in the worldwide. Leukemia, cancer of the hematopoetic cells is the main cause of cancer death in adults and children. Therapeutic agents used in treatment of cancer are known to have narrow therapeutic window and tendency to develop resistance against some cancer cell lines thus, proposing a need to discover some novel agents to treat cancer. In the present study we investigated the anticancer activity of Neosetophomone B(NSP-B), an aquatic fungal metabolite isolated from Neosetophoma sp against leukemic cells (K562 and U937). MTT results demonstrated a dose dependent inhibition of cell proliferation in K562 and U937 cell lines. Annexin staining using flow cytometry indicated that NSP-B treatment cause a dose dependent apoptosis in leukemic cells.Western blot analysis showed that NSP-B mediated apoptosis involves sequential activation of caspase 9, 3 and poly (ADP-ribose) polymerase (PARP) cleavage. Furthermore NSP-B treatment of leukemic cells resulted in upregulation of pro-apoptotic proteins (Bax) with downregulation of anti-apoptotic proteins ( Bcl-2 ).Thus, present study focuses on exploring the mechanism of anticancer activity of NSP-B on leukemic cells, raising the possibility of its use as a novel therapeutic agent for hematological malignancies. Results: We sought to determine whether NSP-B suppresses the growth of leukemic cell lines. We tested a panel of leukemic cell lines with different doses of NSP-B. Cell viability decreased in a concentration-dependent manner in K562 and U937 cell lines. NSP-B induced apoptosis in K562 and U937 cell lines via downregulation of anti-apoptotic proteins and enhancement of pro-apoptotic proteins. NSP-B induced the activation of caspase cascade signaling pathway. Altogether our results suggest that the NSP-B plays an important role in apoptosis in leukemic cell lines .Conclusions: Our data provides insight on anticancer activities of NSP-B in leukemic cell lines (K562 and U937). NSP-B inhibit cell viability via inducing apoptosis. The NSP-B mediated apoptosis occurs via downregulation of anti-apoptotic proteins and enhancement of pro-apototic proteins, thereby activating the caspase-cascade signaling. Further studies are required to elicit role of NSP-B in regulating molecular pathway involved in the progression of cancer. Taken together, above results suggest that NSP-B may have a future therapeutic role in leukemia and possibly other hematological malignancies.