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

Afonso R. M. Almeida, João L. Neto, Ana Cachucho, Mayara Euzébio, Xiangyu Meng, Rathana Kim, Marta B. Fernandes, Beatriz Raposo, Mariana L. Oliveira, Daniel Ribeiro, Rita Fragoso, Priscila P. Zenatti, Tiago Soares, Mafalda R. Matos, Juliana Ronchi Corrêa, Mafalda Duque, Kathryn G. Roberts, Zhaohui Gu, Chunxu Qu, Clara Pereira, Susan Pyne, Nigel J. Pyne, Vasco M. Barreto, Isabelle Bernard-Pierrot, Emannuelle Clappier, Charles G. Mullighan, Ana R. Grosso, J. Andrés Yunes () and João T. Barata ()
Additional contact information
Afonso R. M. Almeida: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
João L. Neto: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Ana Cachucho: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Mayara Euzébio: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Xiangyu Meng: Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer
Rathana Kim: Hematology Laboratory, Saint-Louis Hospital, AP-HP, Paris, France, and Saint-Louis Research Institute, Université de Paris, INSERM U944/Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7212
Marta B. Fernandes: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Beatriz Raposo: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Mariana L. Oliveira: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Daniel Ribeiro: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Rita Fragoso: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Priscila P. Zenatti: Centro Infantil Boldrini
Tiago Soares: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Mafalda R. Matos: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Juliana Ronchi Corrêa: Centro Infantil Boldrini
Mafalda Duque: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa
Kathryn G. Roberts: St. Jude Children’s Research Hospital
Zhaohui Gu: St. Jude Children’s Research Hospital
Chunxu Qu: St. Jude Children’s Research Hospital
Clara Pereira: Smurfit Institute of Genetics, Trinity College Dublin, University of Dublin
Susan Pyne: Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde
Nigel J. Pyne: Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde
Vasco M. Barreto: Universidade NOVA de Lisboa
Isabelle Bernard-Pierrot: Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer
Emannuelle Clappier: Hematology Laboratory, Saint-Louis Hospital, AP-HP, Paris, France, and Saint-Louis Research Institute, Université de Paris, INSERM U944/Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7212
Charles G. Mullighan: St. Jude Children’s Research Hospital
Ana R. Grosso: Universidade NOVA de Lisboa
J. Andrés Yunes: Centro Infantil Boldrini
João T. Barata: Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Interleukin-7 receptor α (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.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-27197-5 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27197-5

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-27197-5

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().