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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Interleukin-7 receptor alpha mutational activation can initiate precursor B-cell acute lymphoblastic leukemia

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Author(s):
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Almeida, Afonso R. M. [1] ; Neto, Joao L. [1] ; Cachucho, Ana [1] ; Euzebio, Mayara [2, 1] ; Meng, Xiangyu [3] ; Kim, Rathana [4, 5] ; Fernandes, Marta B. [1] ; Raposo, Beatriz [1] ; Oliveira, Mariana L. [1] ; Ribeiro, Daniel [1] ; Fragoso, Rita [1] ; Zenatti, Priscila P. [2] ; Soares, Tiago [1] ; de Matos, Mafalda R. [1] ; Correa, Juliana Ronchi [2] ; Duque, Mafalda [1] ; Roberts, Kathryn G. [6, 7] ; Gu, Zhaohui [6, 7] ; Qu, Chunxu [6, 7] ; Pereira, Clara [8] ; Pyne, Susan [9] ; Pyne, Nigel J. [9] ; Barreto, Vasco M. [10] ; Bernard-Pierrot, Isabelle [3] ; Clappier, Emannuelle [4, 5] ; Mullighan, Charles G. [6, 7] ; Grosso, Ana R. [11] ; Yunes, J. Andres [2] ; Barata, Joao T. [1]
Total Authors: 29
Affiliation:
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[1] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon - Portugal
[2] Ctr Infantil Boldrini, Campinas, SP - Brazil
[3] PSL Res Univ, Inst Curie, Equipe Labellisee Ligue Canc, UMR144, Paris - France
[4] St Louis Hosp, AP HP, Hematol Lab, Paris - France
[5] Univ Paris, St Louis Res Inst, Ctr Natl Rech Sci CNRS, Unite Mixte Rech UMR 7212, INSERM U944, Paris - France
[6] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN - USA
[7] St Jude Childrens Res Hosp, Hematol Malignancies Program, Memphis, TN 38105 - USA
[8] Univ Dublin, Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2 - Ireland
[9] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci SIPBS, Glasgow, Lanark - Scotland
[10] Univ Nova Lisboa, NOVA Med Sch, CEDOC Chron Dis Res Ctr, DNA Breaks Lab, Fac Ciencias Med, Lisbon - Portugal
[11] Univ NOVA Lisboa, Fac Ciencias & Tecnol, Dept Ciencias Vida, UCIBIO, Caparica - Portugal
Total Affiliations: 11
Document type: Journal article
Source: NATURE COMMUNICATIONS; v. 12, n. 1 DEC 14 2021.
Web of Science Citations: 0
Abstract

Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia. Interleukin-7 receptor alpha (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy. (AU)

FAPESP's process: 12/03660-9 - Development of therapeutics monoclonal antibodies against mutant IL7R homodimer in Acute Lymphoblastic Leukemia
Grantee:Priscila Pini Zenatti
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 17/02400-7 - Development of an animal model of precursor B-cell acute lymphoblastic leukemia with the oncogenic IL7R mutation
Grantee:Juliana Ronchi Corrêa
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 12/12802-1 - Cooperating mutations, functional studies and antibodies against the mutant IL7R in acute lymphoblastic leukemia
Grantee:José Andrés Yunes
Support type: Regular Research Grants
FAPESP's process: 17/10653-2 - In vivo leukemogenic potential of the mutant CD2-CRE/IL7R
Grantee:Mayara Ferreira Euzébio
Support type: Scholarships abroad - Research Internship - Master's degree
FAPESP's process: 16/07724-2 - In vivo leukemogenic potential of the mutant IL-7R
Grantee:Mayara Ferreira Euzébio
Support type: Scholarships in Brazil - Master
FAPESP's process: 14/20015-5 - Aberrant IL7R signaling in leukemogenesis: from the basics to potential therapeutics
Grantee:José Andrés Yunes
Support type: Regular Research Grants