The role of cohesin mutations in myeloid malignancies development

• Grant number: 14/20861-3
• 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: Niels Olsen Saraiva Câmara
• Grantee: Mariane Tami Amano
• Supervisor abroad: Matthias Merkenschlager
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Local de pesquisa : Imperial College London, England
• Associated to the scholarship: 12/10435-1 - THE INFLUENCE OF MTOR PATHWAY IN MACROPHAGE MODULATION AND ITS CONSEQUENCES IN EXPERIMENTAL CHRONIC KIDNEY DISEASE, BP.PD

Abstract

Cohesin is a multisubunit protein complex initially described to provide stability to sister chromatids during cell division. Recent studies have shown the occurrence of mutations in cohesin in adult myeloid leukemic cells, however, the mechanism of how cohesin could influence on leukemia development is still unclear. Similarly, in children, a high incidence of cohesin components mutations in Down syndrome acute megakaryoblastic leukemia (DS-AMKL) was observed. These evidences together with the fact that cohesins are associated with CTCF regions indicate a possible role of cohesin in gene expression and epigenetic control of myeloid cells. In this project we will investigate the role of cohesin in myeloid cell development using myeloid progenitors from ERt2Cre-Rad21lox/lox mice which will allow us to deplete cohesin (Rad21 subcomponent) at defined stages of macrophage and megakaryocyte differentiation. We will then compare gene expression of wild type macrophages/megakaryocytes with Rad21 depleted cells by RNA-seq. To analyse whether deregulated genes are direct cohesin targets, Rad21 Chip will be performed. A further step to evaluate the influence of cohesin in leukemia development will include a comparison of gene expression between Rad21 depleted macrophages with human adult leukemic cells carrying cohesin mutation, and between Rad21 depleted megakaryocytes with child DS-AMK leukemic cells with cohesin mutation. This project will elucidate the mechanisms of action of cohesin in myeloid cells differentiation, gene expression and chromatin state, and the consequences of cohesin mutations in leukemia development. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CUARTERO, SERGI; WEISS, FELIX D.; DHARMALINGAM, GOPURAJA; GUO, YA; ING-SIMMONS, ELIZABETH; MASELLA, SILVIA; ROBLES-REBOLLO, IRENE; XIAO, XIAOLIN; WANG, YI-FANG; BAROZZI, IROS; DJEGHLOUL, DOUNIA; AMANO, MARIANE T.; NISKANEN, HENRI; PETRETTO, ENRICO; DOWELL, ROBIN D.; TACHIBANA, KIKUE; KAIKKONEN, MINNA U.; NASMYTH, KIM A.; LENHARD, BORIS; NATOLI, GIOACCHINO; FISHER, AMANDA G.; MERKENSCHLAGER, MATTHIAS. Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation. NATURE IMMUNOLOGY, v. 19, n. 9, p. 932+, SEP 2018. Web of Science Citations: 21.