Characterizing the risk for IL-7R-mediated malignancy in different stages of hematopoietic development

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

Publication . Almeida, Afonso; Neto, João Luís; Cachucho, Ana; Euzébio, Mayara; Meng, Xiangyu; Kim, Rathana; Fernandes, Marta; Raposo, Beatriz; Oliveira, Mariana L.; Ribeiro, Daniel; Fragoso, Rita; Zenatti, Priscila P.; Soares, Tiago; Ramos De Matos, Mafalda; Corrêa, Juliana Ronchi; Duque, Mafalda; Roberts, Kathryn G.; Gu, Zhaohui; Qu, Chunxu; Pereira, Clara; Pyne, Susan; Pyne, Nigel J.; Barreto, Vasco M.; Bernard-Pierrot, Isabelle; Clappier, Emannuelle; Mullighan, Charles G.; Grosso, Ana R.; Yunes, J. Andrés; Barata, João T.

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.

2021Artigo científico

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Fundação para a Ciência e a Tecnologia

Número da atribuição

SFRH/BD/147411/2019