An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia

Ifat Geron, Angela Maria Savino, Hila Fishman, Noa Tal, John Brown, Virginia A. Turati, Chela James, Jolanda Sarno, Michal Hameiri-Grossman, Yu Nee Lee, Avigail Rein, Hillary Maniriho, Yehudit Birger, Anna Zemlyansky, Inna Muler, Kara L. Davis, Victoria Marcu-Malina, Nicole Mattson, Oren Parnas, Rabea WagenerUte Fischer, João T. Barata, Catriona H.M. Jamieson, Markus Müschen, Chun Wei Chen, Arndt Borkhardt, Ilan Richard Kirsch, Arnon Nagler, Tariq Enver, Shai Izraeli

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number659
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

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