Identification of genetic factors of response to immunosuppression in acquired aplastic anemia by next generation sequencing

• Grant number: 14/27294-7
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): May 01, 2015
• Effective date (End): November 30, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal researcher: Rodrigo do Tocantins Calado De Saloma Rodrigues
• Grantee: Fernanda Gutierrez Rodrigues
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID
• Associated scholarship(s): 15/19074-0 - Study of genetic factors associated with immunosuppression therapy in acquired aplastic anemia by whole exome sequencing, BE.EP.DR

Abstract

Acquired aplastic anemia (AA) is a rare hematologic disorder defined by pancytopenia with bone marrow hypoplasia. In most patients with AA the destruction of hematopoiesis is due to an immune mechanism dominated by activated cytotoxic T cells that target the hematopoietic progenitors in bone marrow. Hematopoiesis may be restored with bone marrow transplant (BMT) from a matched-sibling donor or intensive immunosuppressive therapy (IST). As most patients are not suitable candidates for BMT or lack a matched-sibling donor, the initial therapy commonly applied is IST with horse anti-thymocyte globulin (ATG), producing hematologic recovery in 60-70% of cases. However, only 34% of patients respond to rabbit ATG, the only formulation available in Brazil, Latin America, and most European countries. Additionally a significant number of patients remain refractory to treatment even after multiple courses of IST. Alterations in nucleotide sequence and in gene regulation suggests a genetic involvement in the immune mechanism of AA and in susceptibility to immunosuppressive therapies. Thus, we aim to study the complete exome of patients with acquired AA in order to identify potential mechanisms that may modulate response to immunosuppression. For this purpose, we will use next generation sequencing (NSG) to determine the whole exome of a group of 10 AA refractory/relapse patients after two couser of immunosuppression and another with 10 AA patients that showed a complete hematologic response after only one course of IST. NGS techniques are useful to identify all genomic variations in coding genes that may contribute to AA phenotype and disease severity. The genome sequences of both groups will be compare to find out genetic variations and patterns shared or exclusive between AA patients. Our study aims to identify genes and genome regions involved in the molecular pathways that may modulate immune response in acquired aplastic anemia and predict responsiveness to treatment. (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)

GUTIERREZ-RODRIGUES, FERNANDA; DONAIRES, FLAVIA S.; PINTO, ANDRE; VICENTE, ALANA; DILLON, LAURA W.; CLE, DIEGO V.; SANTANA, BARBARA A.; PIROOZNIA, MEHDI; IBANEZ, MARIA DEL PILAR F.; TOWNSLEY, DANIELLE M.; KAJIGAYA, SACHIKO; HOURIGAN, CHRISTOPHER S.; COOPER, JAMES N.; CALADO, RODRIGO T.; YOUNG, NEAL S. Pathogenic TERT promoter variants in telomere diseases. Genetics in Medicine, v. 21, n. 7, p. 1594-1602, JUL 2019. Web of Science Citations: 5.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

RODRIGUES, Fernanda Gutierrez. Genetic screening of patients with aplastic anemia by targeting sequencing. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto Ribeirão Preto.