Development of an animal model of precursor B-cell acute lymphoblastic leukemia with the oncogenic IL7R mutation

• Grant number: 17/02400-7
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): June 01, 2017
• Effective date (End): March 03, 2022
• Field of knowledge: Health Sciences - Medicine
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal researcher: José Andrés Yunes
• Grantee: Juliana Ronchi Corrêa
• Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
• Associated scholarship(s): 20/11380-2 - Dissecting the RAS/MEK/ERK pathway downstream the oncogenic IL7R in acute lymphoblastic leukemia, BE.EP.DR

Abstract

Acute lymphocytic leukemia (ALL) is the most common type of cancer in childhood. Eighty five percent of ALL originate from B-cell precursors (B-ALL) and 15% from thymocytes (T-ALL). Different chromosomal alterations and oncogenic mutations are known to interrupt the normal process of cell differentiation and/or induce proliferation. We have recently described oncogenic mutations in the IL7R gene in T-ALL. Mutations of IL7R were also found, but less frequently, in 6.5% of B-ALL belonging to the BCR/ABL1-like subtype. This subtype of ALL has a dismal prognosis. Interestingly, about 70% of the BCR/ABL1-like ALLs carry mutations that, like the IL7R ones, activate the JAK-STAT pathway. Studies have shown that IL7R is required for efficient differentiation of B220 + CD43 + (pro-B) and B220 + CD43- (pre-B) cells. Our preliminary results with a knockin mouse model of the IL7R mutation revealed the occurrence of B-ALL in the animals. In this project we propose to study the IL7R-dependent leukemogenesis process in B lymphocyte precursors. Obtained ALLs will be characterized in terms immunophenoptype, immunoglobulin rearrangement and clonality, engraftment and progression in second recipients. The presence of concurring genetic alterations, gene expression profile and the activation of the different IL7R signal transduction pathways will be evaluated aiming to verify the similarities with a BCR/ABL1-like ALL in humans. (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)

ALMEIDA, AFONSO R. M.; NETO, JOAO L.; CACHUCHO, ANA; EUZEBIO, MAYARA; MENG, XIANGYU; KIM, RATHANA; FERNANDES, MARTA B.; RAPOSO, BEATRIZ; OLIVEIRA, MARIANA L.; RIBEIRO, DANIEL; FRAGOSO, RITA; ZENATTI, PRISCILA P.; SOARES, TIAGO; DE MATOS, MAFALDA R.; CORREA, JULIANA RONCHI; DUQUE, MAFALDA; ROBERTS, KATHRYN G.; GU, ZHAOHUI; QU, CHUNXU; PEREIRA, CLARA; PYNE, SUSAN; PYNE, NIGEL J.; BARRETO, VASCO M.; BERNARD-PIERROT, ISABELLE; CLAPPIER, EMANNUELLE; MULLIGHAN, CHARLES G.; GROSSO, ANA R.; YUNES, J. ANDRES; BARATA, JOAO T. Interleukin-7 receptor alpha mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. NATURE COMMUNICATIONS, v. 12, n. 1 DEC 14 2021. Web of Science Citations: 0.

CURY, NATHALIA MORENO; CAPITAO, REBECA MONIQUE; BORGES DE ALMEIDA, RENAN DO CANTO; ARTICO, LEONARDO LUIS; CORREA, JULIANA RONCHI; SIMAO DOS SANTOS, ERIC FRANCISCO; YUNES, JOSE ANDRES; DUARTE CORREIA, CARLOS ROQUE. Synthesis and evaluation of 2-carboxy indole derivatives as potent and selective anti-leukemic agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 181, NOV 1 2019. Web of Science Citations: 0.