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  • Title: An instructive role for Interleukin-7 receptor α in the development of human B-cell precursor leukemia.
    Author: Geron I, Savino AM, Fishman H, Tal N, Brown J, Turati VA, James C, Sarno J, Hameiri-Grossman M, Lee YN, Rein A, Maniriho H, Birger Y, Zemlyansky A, Muler I, Davis KL, Marcu-Malina V, Mattson N, Parnas O, Wagener R, Fischer U, Barata JT, Jamieson CHM, Müschen M, Chen CW, Borkhardt A, Kirsch IR, Nagler A, Enver T, Izraeli S.
    Journal: Nat Commun; 2022 Feb 03; 13(1):659. PubMed ID: 35115489.
    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.
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