Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia.

Autor: Heltemes-Harris LM; Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA., Hubbard GK; Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA., LaRue RS; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455, USA., Munro SA; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455, USA., Yang R; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455, USA.; The Hormel Institute, University of Minnesota Austin, Austin, MN, 55912, USA., Henzler CM; Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, 55455, USA., Starr TK; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA.; Department of Obstetrics, Gynecology and Women's Health, University of Minnesota, Minneapolis, MN, 55455, USA., Sarver AL; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA., Kornblau SM; Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA., Farrar MA; Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA. farra005@umn.edu.; Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA. farra005@umn.edu.; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, 55455, USA. farra005@umn.edu.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2021 Oct; Vol. 40 (43), pp. 6166-6179. Date of Electronic Publication: 2021 Sep 17.
DOI: 10.1038/s41388-021-02012-z
Abstrakt: The transcription factors PAX5, IKZF1, and EBF1 are frequently mutated in B cell acute lymphoblastic leukemia (B-ALL). We demonstrate that compound heterozygous loss of multiple genes critical for B and T cell development drives transformation, including Pax5 +/- xEbf1 +/- , Pax5 +/- xIkzf1 +/- , and Ebf1 +/- xIkzf1 +/- mice for B-ALL, or Tcf7 +/- xIkzf1 +/- mice for T-ALL. To identify genetic defects that cooperate with Pax5 and Ebf1 compound heterozygosity to initiate leukemia, we performed a Sleeping Beauty (SB) transposon screen that identified cooperating partners including gain-of-function mutations in Stat5b (~65%) and Jak1 (~68%), or loss-of-function mutations in Cblb (61%) and Myb (32%). These findings underscore the role of JAK/STAT5B signaling in B cell transformation and demonstrate roles for loss-of-function mutations in Cblb and Myb in transformation. RNA-Seq studies demonstrated upregulation of a PDK1>SGK3>MYC pathway; treatment of Pax5 +/- xEbf1 +/- leukemia cells with PDK1 inhibitors blocked proliferation in vitro. In addition, we identified a conserved transcriptional gene signature between human and murine leukemias characterized by upregulation of myeloid genes, most notably involving the GM-CSF pathway, that resemble a B cell/myeloid mixed-lineage leukemia. Thus, our findings identify multiple mechanisms that cooperate with defects in B cell transcription factors to generate either progenitor B cell or mixed B/myeloid-like leukemias.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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