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Cooperating mutations, functional studies and antibodies against the mutant IL7R in acute lymphoblastic leukemia

Grant number: 12/12802-1
Support type:Regular Research Grants
Duration: December 01, 2012 - October 31, 2015
Field of knowledge:Health Sciences - Medicine
Principal Investigator:José Andrés Yunes
Grantee:José Andrés Yunes
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Assoc. researchers: Alexandre Eduardo Nowill ; Carlos Lenz Cesar ; Francisco Pereira Lobo ; Jörg Kobarg ; Silvia Regina Brandalise

Abstract

One of the hallmarks of acute lymphoblastic leukemia (ALL) is the presence of chromosomal and genetic abnormalities. In a previous study we described for the first time oncogenic gain-of-function mutations in the alpha chain of IL-7 receptor (IL7Ra), restricted to T-cell ALL (T-ALL) in 9% of patients. Although some genetic mutations are important 'drivers' of oncogenesis, in most cases it is a sum of several mutations that result in fully cell transformation and progression to cancer. Accordingly, several mutations have been shown to act collaboratively in promoting leukemogenesis. In a first line of investigation, we will address whether the IL7Ra mutation, as the first oncogenic event, is sufficient to initiate leukemia and which other mutations are necessary to evolve to a fully leukemia phenotype. A conditional IL7Ra point-mutant mouse line will be developed (third party) and monitored for the occurrence of 'spontaneous' leukemia and defects on thymocytes development. Recurrent association between specific mutations in different patients suggest their functional collaboration. In our previous study, mutations in the IL7Ra were found associated to HOXA genes alterations. In a recent whole genome sequencing study on T-ALL, IL7Ra mutations were found associated with GATA3 mutations and with presence of the SET-NUP214 fusion transcription factor implicated in HOXA aberrant expression. In the present study, ex vivo functional assays will be performed to test the relevance of GATA3 defects and SET-NUP214 expression in term of enhancing the proliferative and survival advantages driven by IL7Ra mutations. Finally, to identify new genetic mutations associated with the mutant IL7Ra defect we aim to sequence the whole exome of our five T-ALL cases positive for the IL7Ra mutation. In a second line of investigation, we aim to study the mechanism and subcellular location of mutant IL7R signalling. In most cases, these IL7Ra mutations introduce an unpaired cysteine in the extracellular juxtamembrane-transmembrane region of the receptor, allowing de novo formation of intermolecular disulfide bonds between mutant IL7Ra subunits, thereby driving constitutive signaling via JAK1/STAT5, and promoting cell survival and proliferation, typical of oncogenic transformation. In this study we aim to delete or insert cysteines at different positions in the extracellular region of the mutant IL7Ra receptor, investigating their effect on dimer/oligomers formation and on downstream signaling capability. Moreover, we aim to identify the subcellular compartment(s) where the mutant IL7Ra is functional. Finally, since in normal cells the IL7R is a heterodimer formed by the IL7Ra and IL2Rg chains, it is possible that the mutant IL7Ra-IL7Ra homodimer could serve as a leukemia-specific antigen, a fact that will be exploited in this study for the development of monoclonal antibodies, as one possible approach to develop new therapeutics for these patients. (AU)

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; PISSINATO, LEONARDO GRANATO; YUNES, JOSE ANDRES. Deleterious and Oncogenic Mutations in the IL7RA. CANCERS, v. 11, n. 12 DEC 2019. Web of Science Citations: 0.
DA SILVA, RODRIGO FERNANDES; CARDOZO, DANIELA MAIRA; LIBANIO RODRIGUES, GISELE OLINTO; DE SOUZA-ARAUJO, CAROLINE NATANIA; MIGITA, NATACHA AZUSSA; LUCCI DE ANGELO ANDRADE, LILIANA APARECIDA; DERCHAIN, SOPHIE; YUNES, JOSE ANDRES; GUIMARAES, FERNANDO. CAISMOV24, a new human low-grade serous ovarian carcinoma cell line. BMC CANCER, v. 17, NOV 13 2017. Web of Science Citations: 0.
DOS SANTOS, ERIC F. S.; CURY, NATHALIA M.; DO NASCIMENTO, TAINARA A.; RAMINELLI, CRISTIANO; CASAGRANDE, GLEISON A.; PEREIRA, CLAUDIO M. P.; SIMIONATTO, EUCLESIO; YUNES, JOSE A.; PIZZUTI, LUCAS. Ultrasound-Promoted Synthesis of 3-(Thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1carboximidamides and Anticancer Activity Evaluation in Leukemia Cell Lines. Journal of the Brazilian Chemical Society, v. 28, n. 2, p. 217+, FEB 2017. Web of Science Citations: 5.
ERIC F. S. DOS SANTOS; NATHÁLIA M. CURY; TAINARA A. DO NASCIMENTO; CRISTIANO RAMINELLI; GLEISON A. CASAGRANDE; CLAUDIO M. P. PEREIRA; EUCLÉSIO SIMIONATTO; JOSÉ A. YUNES; LUCAS PIZZUTI. Ultrasound-Promoted Synthesis of 3-(Thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamides and Anticancer Activity Evaluation in Leukemia Cell Lines. Journal of the Brazilian Chemical Society, v. 28, n. 2, p. 217-224, Fev. 2017.
FERNANDES, MONICA T.; GHEZZO, MARINELLA N.; SILVEIRA, ANDRE B.; KALATHUR, RAVI K.; POVOA, VANDA; RIBEIRO, ANA R.; BRANDALISE, SILVIA R.; DEJARDIN, EMMANUEL; ALVES, NUNO L.; GHYSDAEL, JACQUES; BARATA, JOAO T.; YUNES, JOSE ANDRES; DOS SANTOS, NUNO R. Lymphotoxin-beta receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype. British Journal of Haematology, v. 171, n. 5, p. 736-751, DEC 2015. Web of Science Citations: 9.
MILANI, MATEUS; ALBERTONI LARANJEIRA, ANGELO BRUNELLI; DE VASCONCELLOS, JAIRA FERREIRA; BRANDALISE, SILVIA REGINA; NOWILL, ALEXANDRE EDUARDO; YUNES, JOSE ANDRES. Plasma Hsp90 Level as a Marker of Early Acute Lymphoblastic Leukemia Engraftment and Progression in Mice. PLoS One, v. 10, n. 6 JUN 11 2015. Web of Science Citations: 3.

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