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

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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
Early online dateAug 17 2021
DOIs
StatePublished - Oct 28 2021

Bibliographical note

Funding Information:
We thank A. Rost, for technical assistance with mouse breeding; the University of Minnesota’s Supercomputing Institute for providing computing and bioinformatic resources; Dr. Meinrad Busslinger (Pax5+/−), Dr. Rudolf Grosschedl (Ebf1−/−), Dr. Peter Johnson (Cebpa−/−), Dr. Andrew Wells (Ikzf1−/−) and Dr. David Largaespada (Rosa26LSL- SB11T2/OncxRosa26LSL-SB11) for providing the indicated mouse strains. The results published here are in part based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, phs000218, managed by the NCI. This work was supported by a Cancer Research Institute Investigator award, a Leukemia and Lymphoma Society Scholar award, funding from the UMN Masonic Cancer center and grants from the NIH (RO1 CA232317) to MAF. TKS was supported by grants from the Randy Shaver Cancer Research and Community Fund, NIH NCI (R21 CA216652), and the Masonic Cancer Center. ALS was supported by NCI (CA211249) and Masonic Cancer Center Support Grant (CA077598). SMK was supported by CPRIT MIRA RP 160693 and NIH/NCI P50 CA100632-09.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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