Study of genetic factors associated with immunosuppression therapy in acquired aplastic anemia by whole exome sequencing

• Grant number: 15/19074-0
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): January 11, 2016
• Effective date (End): January 10, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Fernanda Gutierrez Rodrigues
• Supervisor abroad: Neal Stuart Young
• Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Research place: National Institutes of Health, Bethesda (NIH), United States
• Associated to the scholarship: 14/27294-7 - Identification of genetic factors of response to immunosuppression in acquired aplastic anemia by next generation sequencing, BP.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 antithymocyte 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 suggest 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 IST. For this purpose, we will use next generation sequencing (NGS) to determine the whole exome of three groups: 10 AA refractory patients after two courses of immunosuppression, 10 AA patients that showed a complete hematologic response after only one course of IST, and 10 AA patients who evolve to acute myeloid leukemia or myelodysplastic syndrome. The exome sequences will be compared in order to find out genetic variations and patterns either similar or exclusive among AA patients. The results will be validated with the exome sequencing data from a cohort of 52 AA patients from the National Institutes of Healthy (Bethesda, Maryland, USA) under the supervision of Dr. Neal Young. The results generated in this study will be useful for the identification of genes and genome regions involved in the molecular pathways that may modulate immune response in acquired AA 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.

MARSH, JUDITH C. W.; GUTIERREZ-RODRIGUES, FERNANDA; COOPER, JAMES; JIANG, JIE; GANDHI, SHREYANS; KAJIGAYA, SACHIKO; FENG, XINGMIN; IBANEZ, MARIA DEL PILAR F.; DONAIRES, FLAVIA S.; LOPES DA SILVA, JOAO P.; LI, ZEJUAN; DAS, SOMA; IBANEZ, MARIA; SMITH, ALEXANDER E.; LEA, NICHOLAS; BEST, STEVEN; IRELAND, ROBIN; KULASEKARARAJ, AUSTIN G.; MCLORNAN, DONAL P.; PAGLIUCA, ANTHONY; CALLEBAUT, ISABELLE; YOUNG, NEAL S.; CALADO, RODRIGO T.; TOWNSLEY, DANIELLE M.; MUFTI, GHULAM J. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms. BLOOD ADVANCES, v. 2, n. 1, p. 36-48, JAN 9 2018. Web of Science Citations: 11.