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 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 Wagener, Ute Fischer, João T. Barata, Catriona Jamieson, Markus Müschen, Chun‐Wei Chen, Arndt Borkhardt, Ilan R. Kirsch, Arnon Nagler, Tariq Enver, Shai Izraeli
Abstract
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 IL2Rγ null mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34 + CD10 high CD19 + 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.