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Identification and characterization of pathogenic ZNF687 variant in acute myeloid leukemia

ABSTRACT: Analysis of Beat AML sequencing data revealed a recurrent frameshift variant (R939Pfs*Ter36) in Zinc Finger 687 (ZNF687) that was observed in ~1% of patients and has not been previously described. ZNF687 encodes a transcription factor containing DNA binding C2H2 zinc finger and has been studied in select other malignancies, including Paget’s disease of bone that is associated with giant cell tumor (PDB/GCT) and hepatocellular carcinoma. It is part of a network with ZMYND8 and two additional zinc finger proteins, ZNF592 and ZNF532, that associate with H3K4 demethylation machinery and regulates gene transcription. The R939Pfs*Ter36 frameshift induced overexpression of ZNF687 compared with wild-type, and the overexpressed protein was mislocalized to the cytoplasm. We further performed RNA sequencing on HEK293 cells expressing the frameshift variant, wild-type, or a previously identified variant (P937R) that has been reported as a germline ZNF687 variant characterized to predispose to PDB/GCT. We observed the R939Pfs*Ter36 frameshift to induce activation of oxidative phosphorylation, inactivation of histone methylation machinery, and significant downregulation of lysine methyltransferase 2D (KMT2D) compared with wild-type and P937R. Overall, these findings suggest that ZNF687 R939Pfs*Ter36 plays an important role in AML pathogenesis, which could aid in diagnostic precision, and may impact therapeutic responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240600 | GEO | 2024/01/01

REPOSITORIES: GEO

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