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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE148680 | GEO | 2021/09/20

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC8556320 | biostudies-literature

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

Project description:The transcription factors EBF1 and PAX5 are frequently mutated in B cell acute lymphoblastic leukemia (B-ALL). We demonstrate that Pax5+/- x Ebf1+/- compound heterozygous mice develop leukemia with high penetrance. Similar results were seen in Pax5+/- x Ikzf1+/- and Ebf1+/- x Ikzf1+/- mice for B-ALL, or in Tcf7+/- x Ikzf1+/- mice for T cell leukemia. To identify genetic defects that cooperate with Pax5 and Ebf1 compound heterozygosity to initiate leukemia, we carried out a Sleeping Beauty transposon screen. This screen identified a number of cooperating partners including gain-of-function mutations in Stat5 (~65%) and Jak1 (~68%), as well as loss-of-function mutations in Cblb (61%) and Myb (32%). These findings highlight the key role of JAK/STAT5 signaling in cooperating with Pax5 and Ebf1 compound haploinsufficiency to drive B cell transformation. Moreover, these studies pointed to unexpected roles for loss of function mutations in Cblb and Myb in B cell transformation. Subsequent RNA-Seq studies on WT, Pax5+/-, Ebf1+/-, Pax5+/- x Ebf1+/- pre-leukemic, Pax5+/- x Ebf1+/- leukemic cells and Pax5+/- x Ebf1+/- Sleeping Beauty leukemic cells demonstrated upregulation of a PDK1>SGK3>MYC pathway; treatment of Pax5+/- x Ebf1+/- leukemias with PDK1 specific inhibitors blocked their proliferation in vitro. Finally, we identified conserved transcriptional variation in a subset of genes between human leukemias and our mouse B-ALL models. Thus, compound haploinsufficiency for B cell transcription factors likely plays a critical role in transformation of human B cells and suggest that newly developed PDK1 inhibitors may be effective for treating patients characterized by such defects.

2021-09-20 | GSE148678 | GEO

Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia [RNA-seq]

2021-09-20 | GSE148679 | GEO

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

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

| PRJNA625327 | ENA

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

Project description:Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia [variation]

| PRJNA625329 | ENA

Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia [RNA-seq]

Project description:Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia [RNA-seq]

| PRJNA625328 | ENA

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-02-19 | GSE100695 | GEO

The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-06-23 | E-GEOD-70144 | biostudies-arrayexpress

The transcription factors SOX9 and SOX5/SOX6 cooperate genome-wide through super-enhancers to drive chondrogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-06-23 | GSE70144 | GEO

Clr4/Suv39 and RNA quality control factors cooperate to trigger RNAi and suppress antisense RNA

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2011-04-12 | E-GEOD-26999 | biostudies-arrayexpress

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