Publicação

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

Detalhes bibliográficos
Resumo:	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.
Autores principais:	Almeida, Afonso R.M.
Outros Autores:	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.
Assunto:	General Chemistry General Biochemistry,Genetics and Molecular Biology General Physics and Astronomy
Ano:	2021
País:	Portugal
Tipo de documento:	artigo
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade Nova de Lisboa
Idioma:	inglês
Origem:	Repositório Institucional da UNL

Descrição
Resumo:	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.