Clonal hematopoiesis of undetermined potential as a genetic factor in contribution of cardiovascular changes in patients with chronic leukemia in treatment with tyrosine kinase inhibitors

• Grant number: 20/13599-1
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2021
• End date: April 30, 2024
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Israel Bendit
• Grantee: Israel Bendit
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Luciana Nardinelli ; Ricardo Rodrigues Giorgi ; Sabri Saeed Mohammed Ahmed Al-Sanabani
• Associated scholarship(s): 22/01409-9 - Clonal Hematopoiesis of Undetermined Potential as a Genetic Factor in Contribution of Cardiovascular Changes in Patients with Chronic Leukemia in Treatment with Tyrosine Kinase Inhibitors, BP.TT

Abstract

Chronic myeloid leukemia (CML) was the first neoplasm in humans associated with a chromosome rearrangement. It is characterized by the presence of the Philadelphia (Ph)chromosome, resulting from the fusion of part of the proto-oncogene ABL1, on chromosome 9 with the BCR gene, on chromosome 22, generating the BCR-ABL fusion gene. The gene product is a chimeric protein with high tyrosine kinase activity, which plays a central role in the pathogenesis of CML. The BCR-ABL1 gene became an essential target for first targeted therapy, and imatinib the first tyrosine kinase inhibitor(TKI) resulting from the chimeric BCR-ABL1 protein. Approximately 30% of patients with chronic phase CML may present resistance or intolerance to IM requiring the switch to a second-generation TKI such as Dasatinib or Nilotinib. These drugs have a more significant inhibition potential in vitro when compared to imatinib. However, it has been reported a higher incidence of cardiovascular events in patients treated with nilotinib pleural effusion or pulmonary hypertension with dasatinib. The association of somatic mutations in the DNMT3A, TET2, ASXL1, and JAK2 genes has recently been described in both cardiovascular diseases and myeloproliferative neoplasms. Therefore, patients with CML in treatment with second-generation TKI and who have somatic mutations in the above-reported genes would be at a higher risk of cardiovascular disease. Thus, identification of mutations could be beneficial in selecting the best second generation TKI after resistance or intolerance to imatinib. The present study aims to identify mutations in the following genes DNMT3A, TET2, ASXL1, and JAK2 in patients with CML who are receiving imatinib or second generation TKI as dasatinib or nilotinib. Once mutations are identified, we will correlate with the cardiovascular score risk and the calcium score. (AU)