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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia [RNA-seq 2]

ABSTRACT: To investigate usage of exon 8 in ZNF384 in different myeloid/lymphoid populations from MPAL/BALL PDX and cell lines

ORGANISM(S): Homo sapiens

PROVIDER: GSE191028 | 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.

2022-03-16 | PXD028481 | Pride

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.

2022-08-31 | GSE181617 | GEO

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

Project description:We report no global changes in H3K27Ac upon expression of ZNF384 fusions but 47 loci with increased H3K27Ac. Therefore we performed HiChIP H3K27Ac to determine if those loci are enhancers. We did not observe any differential looping.

2022-08-31 | GSE181498 | GEO

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

Project description:RNA-seq of multiple models of ZNF384-rearrangments (transplanted human CD34 cells and transplanted mouse lineage negative cells) to determine differentially expressed genes.

2022-08-31 | GSE181532 | GEO

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

Project description: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.

2022-08-31 | GSE181495 | GEO

ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia

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

2022-08-31 | GSE181499 | GEO

Epigenetic regulation of FLT3 by ZNF384-fusion protein

Project description:Profiling global gene expression in large ALL cohorts, we identified unique over-expression of FLT3 in ZNF384-rearranged ALL, consistently across cases harboring different fusion partners with ZNF384. Mechanistically, we discovered an intergenic enhancer element at the FLT3 locus that is exclusively activated in ZNF384-rearranged ALL, with the enhancer-promoter looping directly mediated by the fusion protein. There was also a striking global enrichment of active enhancers within ZNF384 binding sites across the genome in ZNF384-rearranged ALL cells.

2022-08-11 | GSE197890 | GEO

RNA-sequencing to investigate transcriptional changes caused by ZNF384 fusion proteins in murine pre-B cells

Project description:RNA-sequencing was performed on Arf-/- pre-B cell expressing either wild-type ZNF384, TAF15-ZNF384, or TCF3-ZNF384. We found that pre-B cells that express ZNF384 fusion proteins have a gene expression profile similar to patients with ZNF384-rearranged leukemia.

2018-10-18 | GSE112558 | GEO

ChIP-sequencing to investigate occupancy of wild-type and fusion ZNF384 proteins in murine pre-B cells

Project description:We report the changes in chromatin occupancy between HA-tagged wild-type ZNF384 and the two leukemogenic fusion proteins, TAF15-ZNF384, and TCF3-ZNF384, in Arf-/- pre-B cells. Using ChIP-sequencing we found that 2298 peaks have new or increased binding while 495 peaks have decreased or lost binding of the fusion proteins compared to wild-type ZNF384.

2018-10-18 | GSE112560 | GEO

Multiomic Single Cell Sequencing Identifies Stemlike Nature of Mixed Phenotype Acute Leukemia and Provides Novel Risk Stratification [PIP-seq]

Project description:Mixed phenotype acute leukemia (MPAL) also known as acute leukemia of ambiguous lineage (ALAL), is characterized by leukemic blasts with both lymphoid and myeloid cell surface markers. Here, we use SC multiomic profiling on newly diagnosed MPAL samples to characterize the immunophenotypic, genetic, and transcriptional landscapes of MPAL. This profiling allows us to definitively contradict the paradigm of MPAL as a disease on a continuum with myeloid and lymphoid lineage acute leukemias, and instead identifies MPAL as a distinct, stem-like disease that, unlike other leukemias, cannot be defined by genetics alone. We further describe a stem cell gene expression signature for MPAL that can predict patient survival. These results broaden our understanding of MPAL biology and suggest a path toward novel risk stratification for MPAL. Importantly, these findings have potential to direct treatment and, hopefully, ultimately improve the prognosis of this disease.

2023-08-07 | GSE232073 | GEO

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