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. de Matos, Juliana Ronchi Corrêa, Mafalda Duque, Kathryn G. Roberts, Zhaohui Gu, Chunxu Qu, Clara PereiraSusan Pyne, Nigel J. Pyne, Vasco M. Barreto, Isabelle Bernard-Pierrot, Emannuelle Clappier, Charles G. Mullighan, Ana R. Grosso, J. Andrés Yunes, João T. Barata

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Article number7268
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - Dec 2021

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