Research Grants 14/20015-5 - Oncologia, Transformação celular neoplásica - BV FAPESP
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Aberrant IL7R signaling in leukemogenesis: from the basics to potential therapeutics

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive cancer and the most frequent childhood malignancy, arising from clonal expansion of lymphoid progenitors arrested at different stages of development. Currently, more than 80% of children with ALL, either B or T, are alive and disease-free at 5 years. Remarkable success has been recently achieved with use of imatinib for the treatment of BCR-ABL1 positive ALL, providing a paradigm for new studies aiming at characterizing potentially actionable kinase-altering mutations in ALL. We and others have found that around 10% of T-ALL patients display gain-of-function oncogenic mutations in the IL7R gene. Recent analysis on the high risk Philadelphia-like B-ALL subtype revealed IL7R or other JAK-STAT-pathway activating mutations in 10% and 50% of cases, respectively. In this project we propose to make use of two different, complementary inducible knock-in mouse models of IL7R mutations, which are being generated independently by Dr. Yunes (Brazil) and Dr. Barata (Portugal), to characterize the impact of mutational activation of IL7R on T- and B-cell development and determine whether it has the ability to drive leukemogenesis per se or in cooperation with other oncogenic hits. In parallel, we will screen 3,700 lead molecules, enriched in signal transduction inhibitors, in order to validate new molecular targets and tools for pre-clinical intervention against aberrant IL-7R-mediated signaling in ALL. We expect not only to generate considerable knowledge about the mechanisms, pathways and cellular targets underlying IL7R-mediated transformation in vivo, but also hopefully fulfill our common goal of translating basic knowledge into valid and novel therapeutic tools that may help in ALL treatment. (AU)

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Scientific publications (6)
(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)
CAMPOS, LIVIA WEIJENBORG; ZENATTI, PRISCILA PINI; PISSINATO, LEONARDO GRANATO; RODRIGUES, GISELE O. LIBANIO; ARTICO, LEONARDO LUIS; GUIMARAES, THAIS RAFAEL; ARCHANGELO, LETICIA FROHLICH; MARTINEZ, LEANDRO; BROOKS, ANDREW J.; YUNES, JOSE ANDRES. Oncogenic basic amino acid insertions at the extracellular juxtamembrane region of IL7RA cause receptor hypersensitivity. Blood, v. 133, n. 11, p. 1259-1263, . (12/12802-1, 14/20015-5, 10/16947-9, 13/08293-7)
CAMPOS, LIVIA WEIJENBORG; PISSINATO, LEONARDO GRANATO; YUNES, JOSE ANDRES. Deleterious and Oncogenic Mutations in the IL7RA. CANCERS, v. 11, n. 12, p. 18-pg., . (12/12802-1, 14/20015-5)
CAMPOS, LIVIA WEIJENBORG; PISSINATO, LEONARDO GRANATO; YUNES, JOSE ANDRES. Deleterious and Oncogenic Mutations in the IL7RA. CANCERS, v. 11, n. 12, . (12/12802-1, 14/20015-5)
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; et al. Interleukin-7 receptor alpha mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. NATURE COMMUNICATIONS, v. 12, n. 1, . (12/03660-9, 17/02400-7, 12/12802-1, 17/10653-2, 16/07724-2, 14/20015-5)
ARTICO, LEONARDO LUIS; ALBERTONI LARANJEIRA, ANGELO BRUNELLI; CAMPOS, LIVIA WEIJENBORG; CORREA, JULIANA RONCHI; ZENATTI, PRISCILA PINI; CAMPELLO CARVALHEIRA, JOSE BARRETO; BRAMBILLA, SANDRA REGINA; NOWILL, ALEXANDRE EDUARDO; BRANDALISE, SILVIA REGINA; YUNES, JOSE ANDRES. Physiologic IGFBP7 levels prolong IGF1R activation in acute lymphoblastic leukemia. BLOOD ADVANCES, v. 5, n. 18, p. 3633-3646, . (14/20015-5, 12/12802-1)
ARTICO, LEONARDO LUIS; RUAS, JULIANA SILVEIRA; TEIXEIRA JUNIOR, JOSE RICARDO; MIGITA, NATACHA AZUSSA; SEGUCHI, GUSTAVO; SHI, XINGHUA; BRANDALISE, SILVIA REGINA; CASTILHO, ROGER FRIGERIO; YUNES, JOSE ANDRES. IGFBP7 Fuels the Glycolytic Metabolism in B-Cell Precursor Acute Lymphoblastic Leukemia by Sustaining Activation of the IGF1R-Akt-GLUT1 Axis. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 11, p. 14-pg., . (19/04943-3, 22/04464-0, 17/17728-8, 14/20015-5, 12/12802-1)

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