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.

ORCID iDs

Almeida, Afonso R M, Neto, João L, Cachucho, Ana, Euzébio, Mayara, Meng, Xiangyu, Kim, Rathana, Fernandes, Marta B, Raposo, Beatriz, Oliveira, Mariana L, Ribeiro, Daniel, Fragoso, Rita, Zenatti, Priscila P, Soares, Tiago, de Matos, Mafalda R, Corrêa, Juliana Ronchi, Duque, Mafalda, Roberts, Kathryn G, Gu, Zhaohui, Qu, Chunxu, Pereira, Clara, Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584, Pyne, Nigel J ORCID logoORCID: https://orcid.org/0000-0002-5657-4578, Barreto, Vasco M, Bernard-Pierrot, Isabelle, Clappier, Emannuelle, Mullighan, Charles G, Grosso, Ana R, Yunes, J Andrés and Barata, João T;
CORE (COnnecting REpositories)