ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Abstract

Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

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

“…In contrast to its fusion partners, ZMYND11-MBTD1 favors cell growth/proliferation, likely in part through expression of the MYC oncogene, and inhibits expression of specific differentiation markers. While this work was processed for submission, highly related findings were reported, using expression of the fusion protein in murine HSPCs to show the importance of Tip60 interaction and downstream histone acetylation for leukemogenesis (Li et al, 2021). Furthermore, the onco-histone mutation H3.3G34R in pediatric high grade glioblastoma has been linked to impaired recruitment of ZMYND11 and its repressor function on highly expressed genes, promoting tumorigenesis by stabilizing expression of key progenitor genes (Bressan et al, 2021), which is a mechanism reminiscent of the one described for the fusion.…”

“…Furthermore, the onco-histone mutation H3.3G34R in pediatric high grade glioblastoma has been linked to impaired recruitment of ZMYND11 and its repressor function on highly expressed genes, promoting tumorigenesis by stabilizing expression of key progenitor genes (Bressan et al, 2021), which is a mechanism reminiscent of the one described for the fusion. As mistargeting of the NuA4/TIP60 complex seems to be the main mechanism employed by the ZMYND11-MBTD1 fusion, it can be most interesting to test some specific KAT5/Tip60 HAT inhibitors (Gao et al, 2014) (Coffey et al, 2012) to determine if de novo acetylation at coding regions is indeed the main oncogenic driving force in this specific group of acute myeloid leukemia, as suggested by the parallel study (Li et al, 2021). But for potential therapeutic approaches, inhibiting the HAT activity of KAT5/Tip60 may have large pleiotropic effects due to the essential roles of NuA4/TIP60 in several essential nuclear processes.…”

DOT1L activity in leukemia cells requires interaction with ubiquitylated H2B that promotes productive nucleosome binding

“…Fractionation of cells for the assessment of chromatin association by DOT1L was conducted as previously described ( Li et al, 2021 ). In brief, cells were collected and washed twice with cold PBS, followed by centrifugation at 300 g for 5 min at 4°C.…”

“…Fractionation of cells for the assessment of chromatin association by DOT1L was conducted as previously described (Li et al, 2021).…”

PRC2 Inactivating Mutations in Cancer are Synthetic Lethal with DNMT1 Targeted Therapy via Enhanced Viral Mimicry

“…Coverage bigwig files were created via bamCoverage command from deepTools 84 to normalize to total reads and human genome size, and subsequent ChIP-seq profiles were visualized by either Integrative Genomics Viewer 85 software or by using the plotHeatmap command from deepTools 84 . Genomic regions enriched with H3K27me3 reads were identified using a sliding window method, using input as controls as described previously 86,87 . Genes with peaks in their promoter regions (+/2 kb from TSS) were designated as H3K27em3+ genes.…”