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Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

ABSTRACT: Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

PROVIDER: PRJNA1047125 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27006841_1.fastq.gz	Fastqsanger.gz
	SRR27006841_2.fastq.gz	Fastqsanger.gz
	SRR27006842_1.fastq.gz	Fastqsanger.gz
	SRR27006842_2.fastq.gz	Fastqsanger.gz
	SRR27006843_1.fastq.gz	Fastqsanger.gz

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Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

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.

2024-11-20 | GSE249078 | GEO

Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

2024-11-20 | GSE249076 | GEO

Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

Project description:Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

| PRJNA1047124 | ENA

Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

Project description:Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia

| PRJNA1047121 | ENA

Upfront Menin-inhibitor resistance in multiply pretreated leukemias

Project description:Inhibitors of the Menin-KMT2A interaction are promising agents for the treatment of KMT2A-rearranged (KMT2A-r) leukemias. We evaluated Menin inhibition in patient derived xenografts of KMT2A-r leukemias with high-risk features. Three AMLs with high-risk fusion partners (MLLT10, MLLT4) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreated KMT2A::AFF1 ALL samples were much less sensitive compared to cells obtained earlier in the same patients’ disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway and TP53 mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D has been reported to result in Menin inhibitor resistance, and KMT2C-edited cells from this patient were selected for in VTP containing growth conditions. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.

2025-11-14 | GSE309882 | GEO

UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [RNA-seq]

Project description:UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [RNA-seq]

| PRJNA1272588 | ENA

UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [ChIP-seq]

Project description:UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [ChIP-seq]

| PRJNA1272575 | ENA

BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor

Project description:BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor

| PRJNA1063269 | ENA

Epigenetic regulation of noncanonical menin targets modulates menin inhibitor response in acute myeloid leukemia.

Project description: Not available

| S-EPMC11561541 | biostudies-literature

UBR5 Mediates Menin Inhibitor Dependent Menin/KMT2A Complex Stability [RNA-seq]

Project description:The chromatin adaptor protein Menin (MEN1) is required by acute leukemias driven by mixed lineage leukemia 1 gene rearrangements (KMT2A-r) for sustained leukemogenesis. Menin inhibitors (MIs), which disrupt the Menin-KMT2A interface leading to downregulation of Menin-KMT2A oncogenic transcriptional programs, have shown promising results in recent clinical trials treating acute myeloid leukemia (AML). Decreased Menin protein stability has been observed following treatment with several MIs though proteasomal degradation, though the biological mechanisms that control Menin stability are not well understood. Here we interrogate and compare five clinical MIs and two pre-clinical compounds to characterize the mechanism by which MIs induce Menin degradation and demonstrate that the loss of the Menin-KMT2A interaction results in decreased protein stability of Menin and KMT2A. We have identified the HECT E3 ubiquitin ligase UBR5 as a regulator of Menin protein stability and demonstrate that UBR5 binds to similar sites as the Menin/KMT2A complex on chromatin. Loss of UBR5 leads to transcriptional rescue of Menin-KMT2A target genes leading to decreased sensitivity to all MIs. Thus, we present UBR5 as an important regulator of Menin/KMT2A complex stability and Menin destabilization/subcellular localization as a designable feature of Menin inhibition targeting KMT2A-r leukemias.

2025-08-01 | GSE299103 | GEO

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