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http://hdl.handle.net/10451/51189
Título: | An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia |
Autor: | Geron, Ifat Savino, Angela Maria Fishman, Hila Tal, Noa Brown, John Turati, Virginia A. James, Chela Sarno, Jolanda Hameiri-Grossman, Michal Lee, Yu Nee Rein, Avigail Maniriho, Hillary Birger, Yehudit Zemlyansky, Anna Muler, Inna Davis, Kara L. Marcu-Malina, Victoria Mattson, Nicole Parnas, Oren Wagener, Rabea Fischer, Ute Barata, João T. Jamieson, Catriona H. M. Müschen, Markus Chen, Chun-Wei Borkhardt, Arndt Kirsch, Ilan Richard Nagler, Arnon Enver, Tariq Izraeli, Shai |
Data: | 2022 |
Editora: | Springer Nature |
Citação: | Nat Commun. 2022 Feb 3;13(1):659. |
Resumo: | Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis "ph-like" BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic stem and progenitor cells induces a preleukemic state in transplanted immunodeficient NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolve into BCP-ALL with spontaneously acquired Cyclin Dependent Kinase Inhibitor 2 A (CDKN2A) deletions, as commonly observed in primary human BCP-ALL. CRISPR mediated gene silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA results in robust development of BCP-ALLs in-vivo. Thus, we demonstrate that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL. |
Descrição: | © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Peer review: | yes |
URI: | http://hdl.handle.net/10451/51189 |
DOI: | 10.1038/s41467-022-28218-7 |
Versão do Editor: | https://www.nature.com/ncomms/ |
Aparece nas colecções: | FM - Artigos em Revistas Internacionais IMM - Artigos em Revistas Internacionais |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Role_Interleukin7.pdf | 4,38 MB | Adobe PDF | Ver/Abrir |
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