Advanced search
Start date
Betweenand

Deciphering the role of ASXL1 mutations on driving myeloproliferative neoplasm progression

Grant number: 19/11747-6
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): July 01, 2020
Effective date (End): June 30, 2021
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Fabíola Traina
Grantee:Juan Luiz Coelho da Silva
Supervisor abroad: Ann Mullally
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Research place: Brigham and Women's Hospital (BWH), United States  
Associated to the scholarship:16/23191-4 - Investigation of IRS2 role on the pathogenesis of myeloproliferative neoplasms JAK2V617F using murine models, BP.DR

Abstract

The epigenetic modifier additional sex combs-like 1 (ASXL1) is frequently mutated and associated with a poor prognosis across myeloid neoplasms, including myeloproliferative neoplasms (MPN). Frameshift ASXL1 mutations located in the last exon produce a C-terminally truncated mutant protein that promotes myeloid transformation by altering histone modifications potentially in both a dominant negative or a gain-of-function manner. In myelofibrosis, ASXL1 mutations are frequently identified and associated with advanced-stage disease, bone marrow fibrosis, osteosclerosis and megakaryocytic maturation defects. Our research proposal is focused on deciphering the role of ASXL1 frameshift mutations on driving MPN progression, specifically with respect to perturbing megakaryopoiesis and promoting myelofibrosis. Using a novel knockin mutant Asxl1 mouse model, we plan to ectopically express JAK2V617F and CALRdel52bp in c-Kit-enriched bone marrow cells using a retroviral bone marrow transplant (BMT) model. Mice will be followed for survival, architectural aspects of bone marrow, spleen, liver and lung, blood counts and hematopoietic progenitors' frequency and function using multiparametric flow cytometry and self-renewal capacity and differentiation (ex-vivo and functional assays). We will assess the molecular alterations caused by mutant Asxl1 using CHIP-seq in hematopoietic stem- and progenitor-cells and megakaryocytes. Using megakaryocytic cell lines SET-2 and CHRF-288-11, we will introduce clinically relevant mutations or knockout ASXL1 using CRISPR/Cas9 and evaluate megakaryocytic in vitro differentiation. Molecularly, we will identify the epigenetic changes differentially distributed across the genome using genome-wide CHIP-Seq and gene-sets enrichment following ASXL1 mutation using RNA-seq.

News published in Agência FAPESP Newsletter about the scholarship:
Articles published in other media outlets (0 total):
More itemsLess items
VEICULO: TITULO (DATA)
VEICULO: TITULO (DATA)