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Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes

ABSTRACT: In this study, we characterize the fusion protein produced by the ZMYND11-MBTD1 translocation in acute myeloid leukemia. We express the fusion protein and necessary controls in K562 Cells. The fusion protein assembles ZMYND11 factor with the full acetyltransferase NuA4/TIP60 complex. The fusion protein leads to mislocalization NuA4/TIP60 complex in gene bodies, thereby increasing H4ac in specific gene targets. Finally, chromatin aberration is linked to aberrant gene expression and spliced isoforms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171673 | GEO | 2022/06/01

REPOSITORIES: GEO

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Project description:Endometrial stromal sarcomas (ESSs) are a genetically heterogeneous group of rare uterine neoplasms that are frequently driven by recurrent gene rearrangements. In conventional low-grade ESSs, JAZF1-SUZ12, PHF1-JAZF1, EPC1-PHF1 and MEAF6-PHF1 chimeric fusions have been reported in > 50% of cases. The recently described t(10;17)(q22;p13) translocation yields YWHAE-FAM22A/B chimeric proteins that are associated with histologically high-grade and clinically more aggressive ESS. Integrating whole-transcriptome paired-end RNA sequencing with fluorescence in situ hybridization (FISH) and conventional cytogenetics, we identified MBTD1 (Malignant Brain Tumor Domain-containing 1) and CXorf67 (Chromosome X open reading frame 67) as the genes involved in the novel reciprocal t(X;17)(p11.2;q21.33) translocation in two independent low-grade ESS of classical histology. The presence of the MBTD1-CXorf67 fusion transcript was validated in both cases using RT-PCR followed by Sanger sequencing. A specific FISH assay to be used on paraffin tissues was developed to detect the novel t(X;17) translocation, and resulted in identification of an additional low-grade ESS case positive for the MBTD1-CXorf67 fusion among 14 uterine stromal tumours [9 ESSs and 5 undifferentiated endometrial sarcomas (UESs)] that were negative for JAZF1 and YWHAE rearrangements. Gene expression profiles of 3 ESSs with YWHAE- and 4 classical ESSs with JAZF1-rearrangements, and 4 UESs without known gene rearrangements, indicated clustering of tumours with MBTD1-CXorf67 fusion together with low-grade JAZF1-associated ESSs. The chimeric MBTD1-CXorf67 fusion identifies yet another cytogenetically distinct subgroup of low-grade ESS and offers the opportunity to shed light on the functions of two poorly characterized genes. Genomic DNA extracted from 2 low-grade ESS frozen tumor samples; Agilent CGH+SNP 4x180K array. Reference female DNA supplied with the SureTag Complete DNA Labeling Kit was used for the aCGH experiments.

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Oncogenic ZMYND11-MBTD1 fusion protein anchors the NuA4/TIP60 histone acetyltransferase complex to the coding region of active genes

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