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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.
This dissertation, "Mechanism of Sorafenib Resistance in FLT3-ITD⁺ Acute Myeloid Leukemia" by Cheuk-him, Man, 文卓謙, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by an abnormal increase in myeloblasts in circulation and/or bone marrow. Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene occurs in about 30% of AML and is associated with an inferior prognosis. Tyrosine kinase domain (TKD) mutations occur in about 5% with uncertain prognostic significance. Intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment. However these approaches have reached a deadlock with a cure rate of 30-40%. Targeting FLT3 in AML with multi-tyrosine-kinase inhibitors has been evaluated in Phase II/III clinical trials. Despite an initial clearance of myeloblasts, the leukemia invariably progresses despite continuous treatment. The mechanisms of drug resistance and leukemia progression, hence the effective therapeutic strategies are currently unknown, limiting its clinical application. These issues were addressed in the present study. In the first part, 13 patients with chemo-refractory or relapsed FLT3-ITD+ AML received sorafenib 200-400 mg twice daily of whom 12 patients achieved clearance or near clearance of bone marrow blasts after a median of 27 days (range 21-84 days). There was evidence of myeloid differentiation of the leukemia blasts at remission. Leukemia progression occurred in 9 patients after a median of 72 days (range 54-287 days) and in 4 out of 6 patients it was dominated by clones carrying double FLT3-ITD and -TKD mutations. Microarray studies comparing myeloblasts before sorafenib treatment (sorafenib naive) and at subsequent progression (sorafenib resistant) demonstrated up-regulation of 64 genes including ALDH1A1, JAK3 and TESC whose functions were unknown in AML. Transplantation of sorafenib naive and resistant myeloblasts into NOD/SCID mice recapitulated their clinical behavior when the animals were treated with sorafenib. Both ITD and TKD mutations at D835 were identified in leukemia initiating cells (LICs) from sorafenib naive samples. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations. In the second part, the gene encoding tescalcin (TESC), that was up-regulated at sorafenib resistance and was known to activate a sodium/hydrogen exchange (NHE1), was evaluated to examine its link with TKI resistance. TESC was highly expressed in FLT3-ITD+ AML cell lines MOLM-13 and MV4-11 and its knock-down by siRNA lowered intracellular pH and induced apoptosis. The results were recapitulated by treatment with a NHE1 inhibitor, 5-(N, N-Hexamethylene)amiloride (HMA). Induction of sorafenib resistance in MOLM-13 cell line (MOLM-13-RE) significantly increased its sensitivity to HMA. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD+ AML cells significantly reduced leukemia initiation in NOD/SCID mouse xenotransplantation. Normal CD34+ cells engraftment was not affected. HMA treatment significantly enhanced suppression of FLT3 signaling by sorafenib even in sorafenib resistant cell lines. These observations provided novel information about the pathogenetic role of TESC-NHE1-pHi in sorafenib resistance in AML. In conclusion, the information derived from the present study has provided mechanistic insights to the emergence of drug resistance during sorafenib treatment and important guid
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.
This is the third volume in the new World Health Organization series on histological and genetic typing of tumours. Tumours of the haematopoietic and lymphoid tissues are covered. This was a collaborative project of the European Association for Haematolpathology and the Society for Haematopathology and others. The WHO classification is based on the principles defined in the Revised European-American Classification of Lymphoid Neoplasms (REAL) classification. Over 50 pathologists from around the world were involved in the project and proponents of all major lymphoma and leukaemia classifications have agreed to accept the WHO as the standard classification of haematological malignancies. So this classification represents the first true world wide concensus of haematologic malignancies. Colour photographs, magnetic resonance and ultrasound images and CT scans are included.
Tyrosine Kinase Inhibitors as Sensitizing Agents for Chemotherapy, the fourth volume in the Cancer Sensitizing Agents for Chemotherapy Series, focuses on strategic combination therapies that involve a variety of tyrosine kinase inhibitors working together to overcome multi-drug resistance in cancer cells. The book discusses several tyrosine kinase inhibitors that have been used as sensitizing agents, such as EGFR, BCR-ABL, ALK and BRAF. In each chapter, readers will find comprehensive knowledge on the inhibitor and its action, including its biochemical, genetic, and molecular mechanisms' emphases. This book is a valuable source for oncologists, cancer researchers and those interested in applying new sensitizing agents to their research in clinical practice and in trials. Summarizes the sensitizing role of some tyrosine kinase inhibitors in existing research Brings recent findings in several cancer types, both experimental and clinically, with a particular emphases on underlying biochemical, genetic, and molecular mechanisms Provides an updated and comprehensive knowledge regarding the field of combinational cancer treatment
This book integrates the disciplines of cancer pathology and epidemiology to provide a synergistic and complementary approach to understanding the molecular mechanisms of cancer. This book provides relevant information on the diagnostic, prognostic and predictive molecular pathology of cancer. Epidemiological studies, including descriptive epidemiology, risk factors and molecular mechanisms of disease inform on the etiology and progression of cancer. The text concentrates on major cancers that are currently prevalent and those for which substantial molecular, pathological and epidemiological data is available. Each section is designed to provide an overview of that cancer type in terms of basic biology, review the current epidemiological data surrounding that cancer type and provide information on common practices and challenges related to the molecular pathology of that cancer type. Several relevant techniques in molecular pathology, which facilitate diagnosis and treatment are also explored. Pathology and Epidemiology of Cancer provides a succinct and comprehensive overview of multiple cancer types to guide clinicians during patient care and to guide scientists for innovations in research. It represents an integral resource for pathologists, epidemiologists, medical students as well as translational, basic and clinical science researchers who are all working to progress the field of cancer in terms of diagnosis, treatment and prevention.
In this book, world-renowned experts in the field express well-reasoned opinions on a range of issues and controversies relating to haploidentical transplantation with the aim of providing practicing hematologists with clinically relevant and readily applicable information. Among the areas covered are graft manipulation and methods to control T-cell alloreactivity, the nature of the ideal graft and donor, haploidentical transplantation in pediatric and adult patients with malignant and nonmalignant diseases, immunologic reconstitution following transplantation, complications, and the prevention and treatment of relapse post transplantation. Attention is drawn to the implications of high-impact clinical trials whenever such trials are available. The readily intelligible text is complemented by numerous helpful tables, algorithms, and figures. The book will provide practical support for hematologists and transplant physicians as they attempt to provide optimal care in this exciting but increasingly complex medical specialty.
This book summarizes our current knowledge of MDS, from very basic aspects to the clinical management. It provides guidance to the diagnosis, an understanding of disease mechanisms, and a discussion of treatment strategies.
Written by the foremost authority in the field, this volume is a comprehensive review of the multifaceted phenomenon of hepatotoxicity. Dr. Zimmerman examines the interface between chemicals and the liver; the latest research in experimental hepatotoxicology; the hepatotoxic risks of household, industrial, and environmental chemicals; and the adverse effects of drugs on the liver. This thoroughly revised, updated Second Edition features a greatly expanded section on the wide variety of drugs that can cause liver injury. For quick reference, an appendix lists these medications and their associated hepatic injuries. Also included are in-depth discussions of drug metabolism and factors affecting susceptibility to liver injury.