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Aditional mutations to the PML-RARa gene rearrangement by transcriptome, whole-exome and metilome analysis in Acute Promyelocytic Leukemia samples obtained at diagnosis, molecular remission and relapse time

Grant number: 13/11817-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): December 01, 2013
Effective date (End): November 30, 2018
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Eduardo Magalhães Rego
Grantee:Virgínia Mara de Deus Wagatsuma
Home Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
Associated research grant:13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID
Associated scholarship(s):14/11615-9 - Additional mutations to the PML-RARa gene rearrangement by transcriptome, whole-genome and methylome analysis in Acute Promyelocytic Leukemia samples obtained at diagnosis, molecular remission and relapse time, BE.EP.PD

Abstract

Acute promyelocytic leukemia (APL) is characterized by the infiltration of bone marrow and peripheral blood by leukemic cells presenting a block of differentiation at the stage of promyelocytes. The majority of APL cases (98%) is associated with the t(15;17)(q22;q21) which causes the fusion of two genes: Retinoic Receptor ± (RAR±) and Promyelocytic Leukemia (PML), on chromosomes 17 and 15, respectively. The critical role of PML/RAR± in APL pathogenesis has been demonstrated in transgenic mouse models of the disease. Mice expressing the fusion transcript develop a disease that resembles APL. However, the long latency period required for onset of leukemia suggests that although PML/RAR± is evidently required, it is not alone sufficient to mediate leukemogenesis, and additional genetic events are necessary for progression to overt leukemia. The most important advance in APL treatment have been the therapy with ATRA that is capable to promote cellular differentiation. APL is the first example of differentiation induction therapy and is the most curable form of leukemia. Nevertheless, almost 30% of APL cases progress to relapse. FLT3 mutations and CEBP/a pathway signaling deregulation have been described as additional genetic events secondaries to PML/RARa rearrangement. Mutational patterns that are at high frequency have been correlated to cancer occurrence (driver mutations). Besides genetic mutations, epigenetic changes such as those involving DNA methylation were associated to APL genesis. Nevertheless, the question whether malignant transformation is directly associated with an aberrant DNA methylation pattern or if the abnormal DNA methylation occurs as a secondary contribution remains unanswered. The next generation sequencing (NGS) has been largely used to identify oncogenic patterns. The present study aims to analysis the transcriptome, exome and methylome of APL samples using the NGS technology. Matched samples of the same patient were collected at diagnosis, molecular remission and relapse times, contributing to understand the role of additional mutations and epigenetic alterations with leukemia progression.