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)
Preview |
Text.
Filename: Almeida_etal_NC_2021_mutational_activation_can_initiate_precursor_B_cell_acute_lymphoblastic_leukemia.pdf
Final Published Version License: Download (5MB)| Preview |
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.
-
-
Item type: Article ID code: 79298 Dates: DateEvent14 December 2021Published3 November 2021AcceptedSubjects: Medicine > Therapeutics. Pharmacology Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences Depositing user: Pure Administrator Date deposited: 25 Jan 2022 16:37 Last modified: 09 Apr 2024 02:59 URI: https://strathprints.strath.ac.uk/id/eprint/79298