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ZNF521 enhances MLL-AF9-dependent hematopoietic stem cell transformation in acute myeloid leukemias by altering the gene expression landscape

ABSTRACT: Leukemias derived from the MLL-AF9 rearrangement rely on deranged transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. We demonstrate here that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1 or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage, and acts synergistically when co-expressed with MLL-AF9 throughout the proliferation and expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes upregulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, either at early or late time points of an in vitro model of leukemogenesis. Silencing of ZNF521 in MLL-AF9+ THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining self-renewal of the AML immature compartment, most likely through the perturbation of the gene expression landscape which ultimately favors the expansion of MLL-AF9 transformed leukemic clones.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181006 | GEO | 2022/03/24

REPOSITORIES: GEO

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