AGE-RELATED CHANGES IN HEMATOPOIESIS

Financiador

Organização

Publicações

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

Publication . 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

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.

2022Artigo científico

Acesso aberto

Ver mais

Entidade financiadora

European Commission

Programa de financiamento

H2020

Número da atribuição

813091