Autor(es):
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 ; Pyne, Nigel J. ; Barreto, Vasco M. ; Bernard-Pierrot, Isabelle ; Clappier, Emannuelle ; Mullighan, Charles G. ; Grosso, Ana R. ; Yunes, J. Andrés ; Barata, João T.
Data: 2021
Identificador Persistente: http://hdl.handle.net/10362/130613
Origem: Repositório Institucional da UNL
Assunto(s): Chemistry(all); Biochemistry, Genetics and Molecular Biology(all); Physics and Astronomy(all)
Descrição
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.
