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

Almeida, Afonso R M and Neto, João L and Cachucho, Ana and Euzébio, Mayara and Meng, Xiangyu and Kim, Rathana and Fernandes, Marta B and Raposo, Beatriz and Oliveira, Mariana L and Ribeiro, Daniel and Fragoso, Rita and Zenatti, Priscila P and Soares, Tiago and de Matos, Mafalda R and Corrêa, Juliana Ronchi and Duque, Mafalda and Roberts, Kathryn G and Gu, Zhaohui and Qu, Chunxu and Pereira, Clara and Pyne, Susan and Pyne, Nigel J and Barreto, Vasco M and Bernard-Pierrot, Isabelle and Clappier, Emannuelle and Mullighan, Charles G and Grosso, Ana R and Yunes, J Andrés and Barata, João T (2021) Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. Nature Communications, 12 (1). 7268. ISSN 2041-1723 (https://doi.org/10.1038/s41467-021-27197-5)

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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.

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