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

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

PROVIDER: PRJNA625327 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11546900_1.fastq.gz	Fastqsanger.gz
	SRR11546900_2.fastq.gz	Fastqsanger.gz
	SRR11546901_1.fastq.gz	Fastqsanger.gz
	SRR11546901_2.fastq.gz	Fastqsanger.gz
	SRR11546902_1.fastq.gz	Fastqsanger.gz

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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 [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]

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

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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: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

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

2021-09-20 | GSE148680 | GEO

Ebf1 or Pax5 Haploinsufficiency Synergizes with STAT5 Activation to Initiate Acute Lymphoblastic Leukemia

Project description:STAT5 is critical for differentiation, proliferation and survival of progenitor B cells suggesting a possible role in Acute Lymphoblastic Leukemia (ALL). Herein, we show increased expression of activated STAT5 in ALL patients, which correlates with treatment outcome. Mutations in Ebf1 and Pax5, genes critical for B cell development have also been identified in human ALL. To determine whether mutations in Ebf1 or Pax5 synergize with STAT5 activation to induce ALL we crossed mice expressing a constitutively active form of STAT5 (Stat5b-CA) with mice heterozygous for Ebf1 or Pax5. Haploinsufficiency of either Pax5 or Ebf1 synergized with Stat5b-CA to rapidly induce ALL in 100% of the mice. The leukemic cells displayed reduced expression of both Pax5 and Ebf1 but this had little affect on most EBF1 or PAX5 target genes. However, a subset of these genes was deregulated and included a large percentage of potential tumor suppressor genes and oncogenes. Further, most of these genes appear to be jointly regulated by both EBF1 and PAX5. Our findings suggest a model whereby small perturbations in a self-reinforcing network of transcription factors critical for B cell development, specifically PAX5 and EBF1, cooperate with STAT5 activation to initiate ALL. Gene expression profiling was performed on cells isolated from lymph nodes of Stat5b-CA x Ebf1+/- and Stat5b-CA x Rag2-/- leukemic mice and pre B cells sorted from bone marrow of C57BL/6 mice and Stat5b-CA transgenic mice. 17 Samples.

2011-05-09 | E-GEOD-25645 | biostudies-arrayexpress

PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression

Project description:PHF6 and JAK3 mutations cooperate to drive T-cell acute lymphoblastic leukemia progression

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

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

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Ebf1 or Pax5 Haploinsufficiency Synergizes with STAT5 Activation to Initiate Acute Lymphoblastic Leukemia

2011-05-09 | GSE25645 | GEO