Mutations in BCR-ABL1 and Imatinib resistance in pediatric ALL and CML PH+

• Grant number: 21/09331-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2021
• End date: August 31, 2022
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: José Andrés Yunes
• Grantee: Daniella Pimentel Salomão Safe
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

Leukemia is a malignant disease characterized by uncontrolled proliferation and interruption of the development of leukocyte precursors in the bone marrow. In this project, the Acute Lymphoid Leukemia (ALL) and Chronic Myeloid Leukemia (CML) carrying the translocation t(9; 22) will be studied [BCR-ABL1], which results in the Philadelphia chromosome that is related to high rates of recurrence. This translation causes the expression of the hybrid protein BCR-ABL1. BCR-ABL1, by participating in the leukemogenesis process, and being a tyrosine kinase, has been a target for the development of new inhibitory drugs of this class of proteins, the most common drugs being the first generation Imatinib Mesylate, altered for different diseases neoplastic drugs including ALL and CML, second-generation Desatinib and Nilotinib, child to commonly treat ALL and CML, and third-generation Ponatibib, all of which are BCR-ABL tyrosine kinase inhibitors. Mutations in the kinase domain of BCR-ABL1 are one of the main causes of resistance to treatment with these new drugs. Currently, the Sanger sequencing method (SS) is the most used to observe the presence of these mutations, but a method that hardly allows detecting mutations present in low frequency. Therefore, in this project, we intend to analyze the occurrence of mutations in the coding region of the kinase domain of the BCR-ABL1 gene by NGS (Next-Generation Sequencing). In addition to establishing the methodology and characterizing the spectrum of mutations in our pediatric ALL / CML series, we intend to verify whether the method can be used to quantify the dynamics of mutations over time, for each patient, and their relationship with the onset of drug resistance. (AU)