FACOLTA' DI MEDICINA E CHIRURGIA DOTTORATO DI RICERCA IN EMATOLOGIA XXII Investigation on the mechanisms underlying the chromosomal translocations in therapy-related acute myeloid leukemias

Index Chapter 1: Introduction Page 4 1.1 Acute promyelocytic leukemia (APL) and therapy related APL (t-APL) Page 6 1.2 Therapy related acute myeloid leukemia Page 8 1.3 t-APL following multiple sclerosis and genetic variants of DNA double strand break repair genes Chapter 2: Mechanisms of the formation of t(15;17) in mitoxantrone related therapy related-APL following multiple sclerosis Page 14 Chapter 3: Molecular analysis of the t(15;17) genomic breakpoints in epirubicin associated therapy-related APL following breast carcinoma Page 30 Chapter 4: Analysis of t(15;17) chromosomal breakpoint sequences in therapy-related versus de novo APL Page 41 Chapter 5: Genomic characterization of t(16;21) translocation in therapy-related acute myeloid leukemia Page 49 Chapter 6: To study the genetic markers of susceptibility to t-APL and their association with multiple sclerosis Page 59 Chapter 7: Conclusions and future directions Page 83 4 Chapter 1 Introduction 5 Introduction Therapy-related leukemias are well-recognized clinical syndrome occurring as a late complication following cytotoxic therapy. The term "therapy-related" leukemia is descriptive and based on a patient's history of exposure to cytotoxic agents. Although a causal relationship is implied, the mechanism remains to be proven. These leukemias are thought to be the direct consequence of mutational events induced by cytotoxic therapy, or via the selection of a myeloid clone with a mutator phenotype that has a markedly elevated risk for a mutational event. These types of leukaemias are becoming an increasing healthcare problem as more patients survive their primary cancers. The nature of the causative agent has an important bearing upon the characteristics, biology, time to onset and prognosis of the resultant leukaemia. Agents targeting topoisomerase II induce acute leukaemias with balanced translocations that generally arise within 3 years, often involving the MLL, RUNX1, PML and RARA loci at 11q23, 21q22 15q22 and 17q21 respectively. Chromosomal breakpoints have been found to be preferential sites of topoisomerase II cleavage, which are believed to be repaired by the nonhomologous end-joining DNA repair pathway to generate chimaeric oncoproteins that underlie the resultant leukaemias. Therapy-related acute myeloid leukaemias occurring after exposure to antimetabolites and/or alkylating agents are biologically distinct with a longer latency period, being characterised by more complex karyotypes and loss of p53. The treatment of therapy-related leukaemias represents a considerable challenge due to prior therapy and comorbidities, however, curative therapy is possible, particularly in those with favourable karyotypic features. Although the transforming function of leukemia-associated fusion proteins has been widely studied, little is …