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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 languageAmerican English
Article number659
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - 3 Feb 2022

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