ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency

Cao, Zhendong; Budinich, Krista A.; Huang, Hua; Ren, Diqiu; Lü, Bin; Zhang, Zhen; Chen, Qingzhou; Zhou, Yeqiao; Huang, Yuhan; Alikarami, Fatemeh; Kingsley, Molly C.; Lenard, Alexandra; Wakabayashi, Aoi; Khandros, Eugene; Bailis, Will; Qi, Jun; Carroll, Martin; Blobel, Gerd A.; Faryabi, Robert B.; Bernt, Kathrin M.; Berger, Shelley L.; Shi, Junwei

doi:10.1016/j.molcel.2021.07.018

Cited by 43 publications

(43 citation statements)

References 116 publications

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“…( 22) Inhibition of BRD4 using JQ1 was shown to abolish ZMYND8 occupancy at enhancers. (22) There is compelling evidence that BRD4 functions at replication forks, where it associates with several complexes involved in chromatin remodeling (MMS22L, TONSL) and replication (POLA2, POLD3), which we also observed to be upregulated in our RNA-seq analysis. ( 63 In our time-course assessment of HR repair protein activation following IR, SF10602 ZMYND8 KO displayed prolonged activation of pChk2, while the SF10602 ZMYND8 WT showed a return to baseline 24hrs post-IR.…”

Section: Discussionsupporting

confidence: 55%

“…(16,17) Within the realm of tumor biology, ZMYND8 has been linked to the regulation of cancer-specific programs in colorectal, prostate, breast, H3.3G34R mutant glioma, acute myeloid leukemia, renal cell carcinoma, non-small cell lung cancer (NSCLC), nuclear protein in testis (NUT) carcinoma and hepatocellular carcinoma. (18)(19)(20)(21)(22)(23)(24)(25)(26) Herein, we explore resistance mechanisms reinforced by IDH1 reprogramming that allows tumor cells to survive radiotherapy. We have previously shown, mIDH1 GCCs are more resistant to radiotherapy and that inhibition of mIDH1 using AGI-5198 enhances cellular death following radiation.…”

Section: Introductionmentioning

confidence: 99%

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Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

Carney

Banerjee

Mujeeb

et al. 2022

Preprint

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Mutant isocitrate dehydrogenase 1 (mIDH1) alters the epigenetic regulation of chromatin, leading to a hypermethylation phenotype in adult glioma. Establishment of glioma-specific methylation patterns by mIDH1 reprogramming drives oncogenic features of cancer metabolism, stemness and therapeutic resistance. This work focuses on identifying gene targets epigenetically dysregulated by mIDH1. Treatment of glioma cells with mIDH1 specific inhibitor AGI-5198, upregulated gene networks involved in replication stress. Specifically, we found that the expression of ZMYND8, a regulator of DNA damage response was decreased in three patient-derived glioma cell cultures (GCC) after treatment with AGI-5198. ZMYND8 functions as a chromatin reader to modulate enhancer activity and recruit DNA repair machinery. Knockdown of ZMYND8 expression sensitized mIDH1 GCCs to radiotherapy marked by decreased cellular viability. Following IR, mIDH1 glioma cells with ZMYND8 knockout (KO) exhibit significant phosphorylation of ATM and sustained γH2AX activation. ZMYND8 KO mIDH1 GCCs were further responsive to IR when treated with either BRD4 or HDAC inhibitors. The accumulation of DNA damage in ZMYND8 KO mIDH1 GCCs promoted the phosphorylation of cell cycle checkpoint proteins Chk1 and Chk2. In addition, the recruitment of ZMYND8 to sites of DNA damage has been shown to be PARP-dependent. PARP inhibition further enhanced the efficacy of radiotherapy in ZMYND8 KO mIDH1 glioma cells. These findings indicate the impact of ZMYND8 in the maintenance of genomic integrity and repair of IR-induced DNA damage in mIDH1 glioma. Translational Relevance: Our understanding of radioresistance mechanisms in patient-derived glioma cell cultures (GCC) that endogenously express mIDH1-R132H are limited. We have uncovered a novel gene target Zinc Finger MYND-Type Containing 8 (ZMYND8) that is downregulated following treatment of human mIDH1 GCCs with mIDH1 specific inhibitors. We demonstrate that suppression of ZMYND8 expression by shRNA knockdown or genetic knockout reduces the cellular viability of mIDH1 GCCs to ionizing radiation (IR). Our findings reveal an epigenetic vulnerability of mIDH1 GCCs to ZMYND8 knockout (KO) which results in impaired resolution of IR-induced DNA damage and induction of cell cycle arrest. Additionally, ZMYND8 KO mIDH1 GCCs display increased radiosensitivity to inhibition of epigenetic regulators BRD4, HDAC, and PARP which could be mediated by enhanced replicative stress.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

Carney

Banerjee

Mujeeb

et al. 2022

Preprint

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“…While we observed increased expression of CEBPE after either IRF8, MEF2D, or combined MEF2D/MEF2C knockouts ( Supplemental Data ), our direct transcriptomics data indicate that CEBPE may not be a direct MEF2D target. Similarly, Cao et al (2021) reported that the transcriptional regulator ZMYND8 activates expression of MYC and IRF8, and IRF8 and MEF2D enforce each other's expression. While we did observe decreased IRF8 levels after a prolonged depletion of MEF2D, our data suggest that the reciprocal regulation of IRF8 by MEF2D is either indirect or, as noted above, largely redundant with MEF2C.…”

Section: Discussionmentioning

confidence: 92%

“…Several recent reports have explored the roles of IRF8 and MEF2D in AML ( Cao et al 2021 ; Liss et al 2021 ; Zhao et al 2021 ). In Zhao et al (2021) , MEF2D is reported to inhibit a CEBPE-mediated program of leukemia differentiation.…”

Section: Discussionmentioning

confidence: 99%

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

et al. 2022

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Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.

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“…ZMYND8 is highly expressed in human breast tumors and promotes breast tumor progression in vitro and in xenograft mouse models (12,13,15). Its tumor growth function has been recently characterized in other human cancers, including acute myeloid leukemia, colorectal cancer, glioblastoma, clear cell renal cell carcinoma, bladder cancer, and liver cancer (11,14,(17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

et al. 2022

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27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.

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ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency

Cited by 43 publications

References 116 publications

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

Zinc Finger MYND-Type Containing 8 (ZMYND8) is epigenetically regulated in mutant Isocitrate Dehydrogenase 1 (IDH1) glioma to promote radioresistance

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

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