Proteomics

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ZNF384 fusion oncoproteins drive lineage aberrancy in acute leukemia


ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Evangelia Papachristou  

LAB HEAD: Charles Mullighan

PROVIDER: PXD028481 | Pride | 2022-03-16

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
QE_RIME_EV1.msf Msf
QE_RIME_EV1.raw Raw
QE_RIME_EV2.raw Raw
QE_RIME_EV3.msf Msf
QE_RIME_EV3.raw Raw
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