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Internal tandem duplications in FMS-like receptor tyrosine kinase (FLT3-ITDs) are seen in approximately 25% of all acute myeloid leukemia (AML) patients. FLT3-ITDs induce FLT3 ligand (FL)-independent cellular hyperproliferation, promiscuous and aberrant activation of STAT5, and confer a poor prognosis in patients; however, the molecular mechanisms contributing to FLT3-ITD-induced malignancy remain largely unknown. The protein tyrosine phosphatase, Shp2, is important for normal hematopoiesis as well as hematopoietic stem cell (HSC) differentiation, engraftment, and self-renewal. Furthermore, FLT3-ITD- or constitutive active STAT5-expressing CD34+ cells demonstrate enhanced hematopoietic stem cell self-renewal. Together with the previous findings that Shp2 is critical for normal hematopoiesis, that dysregulated Shp2 function contributes to myeloid malignancies, and that Shp2 has been shown to interact with WT-FLT3 tyrosine 599, which is commonly duplicated in FLT3-ITDs, a positive role for Shp2 in FLT3-ITD-induced signaling and leukemogenesis is implied. I demonstrated that Shp2 is constitutively associated with the reported FLT3-ITDs, N51-FLT3 and N73-FLT3, compared to WT-FLT3; therefore, I hypothesized that increased Shp2 recruitment to N51-FLT3 or N73-FLT3 contributes to hyperproliferation and hyperactivation of STAT5. I also hypothesized that Shp2 cooperates with STAT5 to activate STAT5 transcriptional targets contributing to the up-regulation of pro-leukemic proteins. Finally, I hypothesized that reduction of Shp2 would result in diminished N51-FLT3-induced hyperproliferation and activation of STAT5 in vitro, and prevent FLT3-ITD-induced malignancy in vivo. I found that genetic disruption of Ptpn11, the gene encoding Shp2, or pharmacologic inhibition of Shp2 with the novel Shp2 inhibitor, II-B08, resulted in significantly reduced FLT3-ITD-induced hematopoietic cell hyperproliferation and STAT5 hyperphosphorylation. I also demonstrated a novel role of Shp2 in the nucleus of FLT3-ITD-expressing hematopoietic cells where Shp2 and STAT5 co-localized at the promoter region of STAT5-transcriptional target and pro-survival protein, Bcl-XL. Furthermore, using a Shp2flox/flox;Mx1Cre+ mouse model, I demonstrated that reduced Shp2 expression in hematopoietic cells resulted in an increased latency to and reduced severity of FLT3-ITD-induced malignancy. Collectively, these findings demonstrate that Shp2 plays an integral role in FLT3-ITD-induced malignancy and suggest that targeting Shp2 may be a future therapeutic option for treating FLT3-ITD-positive AML patients.
This book provides a comprehensive and up-to-date review of all aspects of childhood Acute Lymphoblastic Leukemia, from basic biology to supportive care. It offers new insights into the genetic pre-disposition to the condition and discusses how response to early therapy and its basic biology are utilized to develop new prognostic stratification systems and target therapy. Readers will learn about current treatment and outcomes, such as immunotherapy and targeted therapy approaches. Supportive care and management of the condition in resource poor countries are also discussed in detail. This is an indispensable guide for research and laboratory scientists, pediatric hematologists as well as specialist nurses involved in the care of childhood leukemia.
AML is a heterogeneous disease caused by several mutations and cytogenetic abnormalities affecting differentiation and proliferation of myeloid lineage cells. FLT3 is a receptor tyrosine kinase frequently overexpressed or mutated, and its mutations are associated with poor prognosis in AML. Although aggressive chemotherapy followed by hematopoietic stem cell transplant is the current standard of care, the recent approval of targeted therapies, such as FLT3 targeted drugs, is revolutionizing AML treatment that had remained unchanged since the 1970s. As more targeted therapies become available, a personalized treatment approach where therapies are tailored to patients' mutation profiles will likely replace aggressive chemotherapies that are often associated with treatment-related mortality, especially in older patients. However, despite the dramatic clinical response to targeted agents, such as FLT3 inhibitors, remission is almost invariably short-lived and ensued by relapse and drug resistance. Hence, there is an urgent need to understand the molecular mechanisms underlying drug resistance in order to prevent relapse. The overarching aim of this dissertation was to understand the mechanisms by which FLT3 inhibitor-induced molecular alterations promote cell survival, and to identify drugs that can target those pro-survival changes. Recent accumulating evidence points to the presence of a transitional population of cells between the start of treatment and acquisition of mutational resistance, called drug-tolerant 'persisters' (DTPs). DTPs can tolerate an otherwise cytotoxic dose of targeted drug treatment by re-wiring their signaling pathways in response to therapy. The central hypothesis of this dissertation is that DTPs undergo transcriptomic alterations immediately after FLT3 inhibition which not only allow them to survive treatment, but also cause them to be uniquely vulnerable to new drugs as compared to treatment-naïve cells. In Chapter 2 of this dissertation, we sought to delineate the dynamic transcriptomic state associated with DTPs that survive lethal FLT3 inhibition. Our findings suggested that FLT3 targeted drug treatment induces differential expression of approximately 2000 genes in the remaining DTPs. Genes involved in inflammatory pathways were the most significantly up-regulated in DTPs. While this transcriptomic change likely promotes their survival, it also confers on them susceptibility to anti-inflammatory drugs. Indeed, our drug screen revealed that DTPs are particularly sensitive to glucocorticoids. We used different FLT3 mutant AML cell lines, patient cells as well as mouse models to validate that the combination of FLT3 inhibitors and glucocorticoids induces a synergistic cell death. In-silico prediction of upstream regulators of the up-regulated genes revealed that inflammatory transcription factors, including NF-[kappa]B, STAT3 and CIITA are activated. We confirmed that DTPs have an increased activation of NF-[kappa]B as compared to treatment naïve cells. In Chapter 3 of this dissertation, we dissect the mechanism by which glucocorticoids and FLT3 inhibitors synergize. We found that FLT3 inhibition causes the up-regulation of glucocorticoid receptor making DTPs susceptible to glucocorticoids. Furthermore, we demonstrated that glucocorticoids act through glucocorticoid receptor to increase the expression of the pro-apoptotic protein Bim and up-regulate the degradation of the anti-apoptotic protein Mcl-1. Together, our data demonstrate that disequilibrium between Bim and Mcl-1 is the key mechanism by which the combination of FLT3 inhibitors and glucocorticoids synergize to augment cell death. In summary, in this dissertation, we have uncovered that the combination of FLT3 inhibitors and glucocorticoids is a novel potential treatment strategy that can eliminate or minimize minimal residual disease and thereby prevent relapse in FLT3 mutant AML patients. This has a significant clinical implication because glucocorticoids have been in clinical use for decades, and hence, the proposed combination therapy can be explored and translated rapidly to improve patient outcome.
B-Cell precursor acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children. Recently, we and others described a new subtype of the disease, affecting 60% of children with Down Syndrome (DS) and about 10% of patients with sporadic ALL, in which chromosomal rearrangements result in over-expression of the cytokine receptor-like factor 2 (CRLF2) receptor1-4. This over-expression is often accompanied by mutations in additional proteins in the CRLF2 pathway, such as JAK2, a downstream effector in the pathway5-9, and IL7RA, the second subunit in the TSLP receptor10. Based on mutation analyses, aberrant CRLF2 expression was thought to play a causal role in the development of B-ALL. While some data obtained in mouse systems support this assertion2,3,6, no studies have been performed in human cells to ascertain whether or not CRLF2 contributes to B-ALL pathogenesis. Due to the prominent difference between mouse and human B lymphoid development, particularly in the TSLP/IL7 pathways, it is important to study the contribution of activation of the TSLP pathway to the development of B-ALL in human cells. In the research described here, I hypothesized that aberrant expression of CRLF2 in cooperation with secondary mutations in the TSLP pathways contributes to B-ALL initiation. This hypothesis was tested primarily by utilizing cord-blood (CB) hematopoietic-progenitors transduced with a set of lentiviral vectors carrying CRLF2 alone or in combination with JAK2 or IL7RA mutations. Outcome of forced TSLP pathway activation was cell context specific. Expression of CRLF2 in CB hematopoietic-progenitors from a ubiquitous promoter resulted in skewed differentiation towards the myeloid lineage while transcription of the same genes from a B-cell-specific promoter accelerated B-lymphoid differentiation in vitro, underscoring the importance of expressing the genes of interest in the right cellular context for B-ALL pathogenesis. Transduced CB cells were transplanted in NOD/LtSz-scid IL2R[gamma]null (NSG) mice, which are known to support human B-Cell differentiation. Transplanted cells expressing CRLF2 with mutant IL7RA exhibited population expansion, enhanced B-cell differentiation, and a significant block in differentiation at the pro-pre B-cell stage, resembling the stage of differentiation of leukemic blast cells.
Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation: Models in Discovery and Translation, Second Edition once again provides clinical and scientific researchers with a deep understanding of the current research in this field and the implications for translational practice. By providing an overview of the immune biology of HSCT, an explanation of immune rejection, and detail on antigens and their role in HSCT success, this book embraces biologists and clinicians who need a broad view of the deeply complex processes involved. It then moves on to discuss the immunobiology mechanisms that influence graft-versus-host disease (GVHD), graft-versus-leukemia effect, and transplantation success. Using illustrative figures, highlighting key issues, describing recent successes, and discussing unanswered questions, this book sums up the current state of HSCT to enhance the prospects for the future. The second edition is fully revised and includes new chapters on microbiome, metabolism, kinase targets, micro-RNA and mRNA regulatory mechanisms, signaling pathways in GVHD, innate lymphoid system development, recovery and function in GVHD, genetically engineered T-cell therapies, immune system engagers for GVHD and graft-versus-tumor, and hematopoietic cell transplant for tolerance induction in solid organ grafts. Brings together perspectives from leading laboratories and clinical research groups to highlight advances from bench to the bedside Guides readers through the caveats that must be considered when drawing conclusions from studies with animal models before correlating to clinical allogeneic hematopoietic stem cell transplantation (HSCT) scenarios Categorizes the published advances in various aspects of immune biology of allogeneic HSCT to illustrate opportunities for clinical applications
While survival rates for children with cancer have increased in recent times, the increased use of more aggressive therapies has brought with it significant adverse effects. Therefore, the aim of pediatric oncologists has become to achieve "cure at least cost" by the appropriate reduction of the intensity and/or duration of treatment in carefully identified good prognosis patients. By comprehensively covering these issues, this handbook aims to provide residents in pediatric hematology and oncology, as well as staff in related medical or other healthcare disciplines, with an easily accessible source of information about the basic principles of childhood cancer and leukemia, as well as much of the more detailed specialist knowledge required to care for children with these conditions. Divided into sections to allow quick access to the necessary information, the handbook covers general principles of diagnosis and treatment, short and long term care, and oncological emergencies before moving on to chapters on specific disease. Normal values and useful websites are also included for reference.
''An exciting glance at key issues in contemporary hematopoiesis.'' -The Quarterly Review of Biology