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

Lynn M. Heltemes-Harris, Gregory K. Hubbard, Rebecca S. LaRue, Sarah A. Munro, Rendong Yang, Christine M. Henzler, Timothy K. Starr, Aaron L. Sarver, Steven M. Kornblau, Michael A. Farrar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6166-6179
Number of pages14
JournalOncogene
Volume40
Issue number43
DOIs
StatePublished - Oct 28 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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