| Full text | |
| Author(s): Show less - |
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]
Total Authors: 29
|
| Affiliation: Show less - | [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
Total Affiliations: 11
|
| Document type: | Journal article |
| Source: | NATURE COMMUNICATIONS; v. 12, n. 1 DEC 14 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
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) | |
| FAPESP's process: | 12/03660-9 - Development of therapeutics monoclonal antibodies against mutant IL7R homodimer in Acute Lymphoblastic Leukemia |
| Grantee: | Priscila Pini Zenatti |
| Support type: | Scholarships in Brazil - Post-Doctorate |
| FAPESP's process: | 17/02400-7 - Development of an animal model of precursor B-cell acute lymphoblastic leukemia with the oncogenic IL7R mutation |
| Grantee: | Juliana Ronchi Corrêa |
| Support type: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 12/12802-1 - Cooperating mutations, functional studies and antibodies against the mutant IL7R in acute lymphoblastic leukemia |
| Grantee: | José Andrés Yunes |
| Support type: | Regular Research Grants |
| FAPESP's process: | 17/10653-2 - In vivo leukemogenic potential of the mutant CD2-CRE/IL7R |
| Grantee: | Mayara Ferreira Euzébio |
| Support type: | Scholarships abroad - Research Internship - Master's degree |
| FAPESP's process: | 16/07724-2 - In vivo leukemogenic potential of the mutant IL-7R |
| Grantee: | Mayara Ferreira Euzébio |
| Support type: | Scholarships in Brazil - Master |
| FAPESP's process: | 14/20015-5 - Aberrant IL7R signaling in leukemogenesis: from the basics to potential therapeutics |
| Grantee: | José Andrés Yunes |
| Support type: | Regular Research Grants |