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UTX Loss Alters Therapeutic Responses in KMT2A-rearranged Acute Myeloid Leukemia [ChIP-seq]

ABSTRACT: Acute myeloid leukemias (AML) patients bearing chromosomal rearrangements of KMT2A or MLL gene (KMT2A -r) have poor overall survival. Recently, compounds targeting the KMT2A fusion protein complex, such as DOT1L and Menin inhibitors, have shown promising pre-clinical efficacy. Yet, molecular regulators of the anti-tumor activities of these agents remain poorly studied. UTX is a histone H3K27 demethylase with recurrent loss-of-function mutations in human cancers including leukemia. UTX-null leukemia shows greater resistance to chemotherapy agents. However, the impact of UTX on drug resistance of KMT2A -r AML has not been explored. Through a epigenetic compound screen, we identified a unique role of UTX in the regulation of DOT1L and Menin therapies in KMT2A-r AML. Loss of UTX confers resistance to DOT1L and Menin inhibition in an MLL target gene-independent manner. Mechanistically, We show that UTX is required for activation of myeloid differentiation programs induced by DOT1L inhibition. We also revealed BCL2A1 as a target of UTX. Depletion of UTX increased vulnerability to BCL2 inhibitor venetoclax in vitro and in vivo, and combinational treatment of venetoclax could overcome the therapeutic resistance to DOT1L inhibition caused by UTX loss. Our study provides new insights into the role of UTX in therapeutic responses in KMT2A-r AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214274 | GEO | 2022/11/01

REPOSITORIES: GEO

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UTX Loss Alters Therapeutic Responses in KMT2A-rearranged Acute Myeloid Leukemia [RNA-seq]

Project description:Acute myeloid leukemias (AML) patients bearing chromosomal rearrangements of KMT2A or MLL gene (KMT2A -r) have poor overall survival. Recently, compounds targeting the KMT2A fusion protein complex, such as DOT1L and Menin inhibitors, have shown promising pre-clinical efficacy. Yet, molecular regulators of the anti-tumor activities of these agents remain poorly studied. UTX is a histone H3K27 demethylase with recurrent loss-of-function mutations in human cancers including leukemia. UTX-null leukemia shows greater resistance to chemotherapy agents. However, the impact of UTX on drug resistance of KMT2A -r AML has not been explored. Through a epigenetic compound screen, we identified a unique role of UTX in the regulation of DOT1L and Menin therapies in KMT2A-r AML. Loss of UTX confers resistance to DOT1L and Menin inhibition in an MLL target gene-independent manner. Mechanistically, We show that UTX is required for activation of myeloid differentiation programs induced by DOT1L inhibition. We also revealed BCL2A1 as a target of UTX. Depletion of UTX increased vulnerability to BCL2 inhibitor venetoclax in vitro and in vivo, and combinational treatment of venetoclax could overcome the therapeutic resistance to DOT1L inhibition caused by UTX loss. Our study provides new insights into the role of UTX in therapeutic responses in KMT2A-r AML.

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UTX Loss Alters Therapeutic Responses in KMT2A-rearranged Acute Myeloid Leukemia

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Project description:Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent leukemia cells to Menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to the BCL2 inhibition, and combinational treatment of venetoclax overcomes the resistance to Menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.

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