TY - JOUR
T1 - Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia
AU - Heltemes-Harris, Lynn M.
AU - Hubbard, Gregory K.
AU - LaRue, Rebecca S.
AU - Munro, Sarah A.
AU - Yang, Rendong
AU - Henzler, Christine M.
AU - Starr, Timothy K.
AU - Sarver, Aaron L.
AU - Kornblau, Steven M.
AU - Farrar, Michael A.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/10/28
Y1 - 2021/10/28
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-021-02012-z
DO - 10.1038/s41388-021-02012-z
M3 - Article
C2 - 34535769
AN - SCOPUS:85115271536
SN - 0950-9232
VL - 40
SP - 6166
EP - 6179
JO - Oncogene
JF - Oncogene
IS - 43
ER -