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

• Grant number: 14/11615-9
• Support type: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): January 01, 2015
• Effective date (End): December 31, 2015
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Eduardo Magalhães Rego
• Grantee: Virgínia Mara de Deus Wagatsuma
• Supervisor abroad: Christopher Edward Mason
• 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
• Local de pesquisa : Weill Cornell Medical College, United States
• Associated to the scholarship: 13/11817-8 - 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, BP.PD

Abstract

The t(15;17)(q24;q21), generates a PML-RARa fusion gene, the hallmark of acute promyelocytic leukemia (APL), characterized by the infiltration of bone marrow and peripheral blood by leukemic cells presenting a block of differentiation at the stage of promyelocytes. The critical role of PML/RARa in APL pathogenesis has been demonstrated in transgenic mouse models by the observation of a disease with clinical and morphological features of human APL. However, the long latency period with a low penetrance required for onset of leukemia suggests that although PML/RARa is evidently required, it is not alone sufficient to mediate leukemogenesis. Thus, these data suggest that PML/RARa cooperates with secondary mutations for the full leukemic phenotype development. APL is the first example of differentiation induction therapy and is the 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 secondary 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) represents a powerful tool for the discovery of genetic alterations and oncogenic patterns at high resolution. The present study aims to analysis the transcriptome, whole-genome 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. (AU)