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

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Almeida, Afonso R. M. ^[1] ; Neto, Joao L. ^[1] ; Cachucho, Ana ^[1] ; Euzebio, Mayara ^{[2, 1]} ; Meng, Xiangyu ^[3] ; Kim, Rathana ^{[4, 5]} ; Fernandes, Marta B. ^[1] ; Raposo, Beatriz ^[1] ; Oliveira, Mariana L. ^[1] ; Ribeiro, Daniel ^[1] ; Fragoso, Rita ^[1] ; Zenatti, Priscila P. ^[2] ; Soares, Tiago ^[1] ; de Matos, Mafalda R. ^[1] ; Correa, Juliana Ronchi ^[2] ; Duque, Mafalda ^[1] ; Roberts, Kathryn G. ^{[6, 7]} ; Gu, Zhaohui ^{[6, 7]} ; Qu, Chunxu ^{[6, 7]} ; Pereira, Clara ^[8] ; Pyne, Susan ^[9] ; Pyne, Nigel J. ^[9] ; Barreto, Vasco M. ^[10] ; Bernard-Pierrot, Isabelle ^[3] ; Clappier, Emannuelle ^{[4, 5]} ; Mullighan, Charles G. ^{[6, 7]} ; Grosso, Ana R. ^[11] ; Yunes, J. Andres ^[2] ; Barata, Joao T. ^[1]

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^[1] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon - Portugal

^[2] Ctr Infantil Boldrini, Campinas, SP - Brazil

^[3] PSL Res Univ, Inst Curie, Equipe Labellisee Ligue Canc, UMR144, Paris - France

^[4] St Louis Hosp, AP HP, Hematol Lab, Paris - France

^[5] Univ Paris, St Louis Res Inst, Ctr Natl Rech Sci CNRS, Unite Mixte Rech UMR 7212, INSERM U944, Paris - France

^[6] St Jude Childrens Res Hosp, Dept Pathol, Memphis, TN - USA

^[7] St Jude Childrens Res Hosp, Hematol Malignancies Program, Memphis, TN 38105 - USA

^[8] Univ Dublin, Trinity Coll Dublin, Smurfit Inst Genet, Dublin 2 - Ireland

^[9] Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci SIPBS, Glasgow, Lanark - Scotland

^[10] Univ Nova Lisboa, NOVA Med Sch, CEDOC Chron Dis Res Ctr, DNA Breaks Lab, Fac Ciencias Med, Lisbon - Portugal

^[11] Univ NOVA Lisboa, Fac Ciencias & Tecnol, Dept Ciencias Vida, UCIBIO, Caparica - Portugal

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 12, n. 1 DEC 14 2021.
• Citações Web of Science: 0

Resumo

Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia. Interleukin-7 receptor alpha (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. (AU)

• Processo FAPESP: 12/03660-9 - Desenvolvimento de anticorpos monoclonais terapêuticos contra o homodímero IL7R mutante da Leucemia Linfóide Aguda
• Beneficiário: Priscila Pini Zenatti Salles
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/02400-7 - Estabelecimento de um modelo animal de leucemia linfóide aguda B-derivada com mutação oncogênica do IL7R
• Beneficiário: Juliana Ronchi Corrêa
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/12802-1 - Mutações cooperantes, caracterização funcional e anticorpos contra o mutante do IL7R na leucemia linfóide aguda
• Beneficiário: José Andrés Yunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/10653-2 - Estudo da leucemogênese em camundongos CD2-CRE/IL7R mutante
• Beneficiário: Mayara Ferreira Euzébio
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Mestrado
• Processo FAPESP: 16/07724-2 - Potencial leucemogênico do IL-7R mutante in vivo
• Beneficiário: Mayara Ferreira Euzébio
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 14/20015-5 - Sinalização aberrante do IL7R e leucemogênese: ciência básica e pesquisa de potencial terapia
• Beneficiário: José Andrés Yunes
• Modalidade de apoio: Auxílio à Pesquisa - Regular