| First Author | Heltemes-Harris LM | Year | 2021 |
| Journal | Oncogene | Volume | 40 |
| Issue | 43 | Pages | 6166-6179 |
| PubMed ID | 34535769 | Mgi Jnum | J:312446 |
| Mgi Id | MGI:6790330 | Doi | 10.1038/s41388-021-02012-z |
| Citation | Heltemes-Harris LM, et al. (2021) Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia. Oncogene 40(43):6166-6179 |
| abstractText | 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. |
