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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia [scRNA-Seq]

ABSTRACT: Expression of ZNF384 fusions results in lineage abberancy and leukemia development. Here we report the gene expression changes that occur in the hematopoietic system when Ep300-Zfp384 is expressed in a transgenic mouse model.

ORGANISM(S): Mus musculus

PROVIDER: GSE181495 | GEO | 2022/08/31

REPOSITORIES: GEO

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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia

Project description:ZNF384-rearranged fusion oncoproteins (FO) define a subset of lineage ambiguous leukemias, but the mechanistic role of ZNF384 FO in leukemogenesis and lineage ambiguity is poorly understood. Here, using viral expression in mouse and human hematopoietic stem and progenitor cells (HSPCs) and a Ep300-Zfp384 mouse model we show that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing, and self-renewal. In mouse HSPCs, concomitant lesions such as NRASG12D, were required for fully penetrant leukemia, whereas expression of ZNF384 FO drove development of B/myeloid leukemia in human HSPCs, with sensitivity of human ZNF384r leukemia to FLT3 inhibition in vivo. Mechanistically, ZNF384 FO occupy a subset of predominantly intragenic/enhancer regions with increased histone 3 lysine acetylation suggesting enhancer function. These data define a paradigm for FO-driven lineage ambiguous leukemia, in which expression in HSPCs results in deregulation of lineage-specific genes and hematopoietic skewing, progressing to full leukemic transformation in the presence of proliferative stress.

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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia [ChIP-seq]

Project description:We report changes in chromatin occupancy dependent on TCF3-ZNF384 splicing isoform usage. The isoform including exon 8, which encodes 2 zinc finger domains, has increased binding near genes important for nomal hematopoiesis. We report no global changes in H3K27Ac upon expression of ZNF384 fusions but 47 loci with increased H3K27Ac.

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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia [HiChIP]

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ZNF384 Fusion Oncoproteins Drive Lineage Aberrancy in Acute Leukemia.

Project description:ZNF384-rearranged fusion oncoproteins (FO) define a subset of lineage ambiguous leukemias, but their mechanistic role in leukemogenesis and lineage ambiguity is poorly understood. Using viral expression in mouse and human hematopoietic stem and progenitor cells (HSPC) and a Ep300::Znf384 knockin mouse model, we show that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing, and self-renewal. In mouse HSPCs, concomitant lesions, such as NRASG12D, were required for fully penetrant leukemia, whereas in human HSPCs, expression of ZNF384 FO drove B/myeloid leukemia, with sensitivity of a ZNF384-rearranged xenograft to FLT3 inhibition in vivo. Mechanistically, ZNF384 FO occupy a subset of predominantly intragenic/enhancer regions with increased histone 3 lysine acetylation and deregulate expression of hematopoietic stem cell transcription factors. These data define a paradigm for FO-driven lineage ambiguous leukemia, in which expression in HSPCs results in deregulation of lineage-specific genes and hematopoietic skewing, progressing to full leukemia in the context of proliferative stress.SignificanceExpression of ZNF384 FO early in hematopoiesis results in binding and deregulation of key hematopoietic regulators, skewing of hematopoiesis, and priming for leukemic transformation. These results reveal the interplay between cell of origin and expression of ZNF384 FO to mediate lineage ambiguity and leukemia development. This article is highlighted in the In This Issue feature, p. 171.

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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia

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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia

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