Biochemical and biophysical characterization of PML-RARA somatic mutations

• Grant number: 23/04913-2
• Support Opportunities: Scholarships abroad - Research Internship - Scientific Initiation
• Start date: July 22, 2023
• End date: November 21, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: José Andrés Yunes
• Grantee: Mikaela Teodoro
• Supervisor: Albane Coirier Le Maire
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Institution abroad: Centre de Biochimie Structurale de Montpellier (CBS), France
• Associated to the scholarship: 22/06635-7 - PML-RARA mutations and ATRA resistance in pediatric acute promyelocytic leukemia, BP.IC

Abstract

Acute Promyelocytic Leukemia (APL) is characterized by presence of the chromosomal translocation t(15;17) which generates the PML RARA fusion protein. All-trans retinoic acid (ATRA) is one of the main components used for APL treatment. Mutations in the ligand-binding domain (LBD) of the fused RARa nuclear receptor have been associated to ATRA resistance. We sequenced diagnostic and relapse samples from APL patients by next-generation sequencing (NGS). Different LBD domain mutations of the fused RARA transcript were found, including known mutations, like the R272Q, and some novel ones, like the N314D. Some of these mutations may be involved in ligand binding and/or corepressor binding. The (dis)association of co-regulators with PML-RARA and ATRA binding are important for transcriptional regulation and induction of promyelocyte differentiation into mature cells. In this way, our aim is to perform the biochemical and biophysical characterization of these PML-RARA mutations, verifying their effects on ligand binding and coregulator binding. Detailed characterization of these mutants may help determine their role in ATRA resistance while describing the molecular basis for this resistance thus contributing to monitoring, preventing and/or overcoming treatment refractoriness. (AU)