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IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

ABSTRACT: Genome-scale functional genetic screening was utilized to identify resistance mechanisms and synthetic lethal interactions during small molecule targeting of MENIN and DOT1L in MLL1-rearranged AML. Chromatin regulatory complexes are found to modulate the therapeutic response to these inhibitors, and IKZF1/IKAROS is identified as an essential transcriptional regulator that supports leukemia gene expression through extensive chromatin co-occupancy with MENIN and the transcription factor MEIS1. Furthermore, we show that combined IKAROS degradation with imide drugs and MENIN inhibition using VTP-50469 leads to synergistic anti-leukemic effects through rapid induction of apoptotic cell death both in vitro and in vivo. This study uncovers a previously underappreciated role for IKAROS in AML and cooperativity among IKAROS, MLL1/MENIN and MEIS1 in maintaining leukemogenic transcription.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Eric Fischer

LAB HEAD: Eric Fischer

PROVIDER: PXD025229 | Pride | 2022-03-11

REPOSITORIES: Pride

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IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

Project description:Genome-scale functional genetic screening was utilized to identify resistance mechanisms and synthetic lethal interactions during small molecule targeting of MENIN and DOT1L in MLL1-rearranged AML. Chromatin regulatory complexes are found to modulate the therapeutic response to these inhibitors, and IKZF1/IKAROS is identified as an essential transcriptional regulator that supports leukemia gene expression through extensive chromatin co-occupancy with MENIN and the transcription factor MEIS1. Furthermore, we show that combined IKAROS degradation with imide drugs and MENIN inhibition using VTP-50469 leads to synergistic anti-leukemic effects through rapid induction of apoptotic cell death both in vitro and in vivo. This study uncovers a previously underappreciated role for IKAROS in AML and cooperativity among IKAROS, MLL1/MENIN and MEIS1 in maintaining leukemogenic transcription.

2022-03-11 | PXD025232 | Pride

IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

2022-03-11 | PXD025228 | Pride

IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

2022-03-11 | PXD025227 | Pride

IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

2022-03-11 | PXD025230 | Pride

IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

2022-03-11 | PXD025231 | Pride

IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

2022-03-11 | PXD025272 | Pride

IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia

2022-03-11 | PXD025271 | Pride

Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia

Project description:Small molecules that target the MENIN-KMT2A protein-protein interaction (Menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A, MLL1) rearranged (KMT2A-r) and nucleophosmin mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with Lenalidomide or Iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. Recently, the novel IKAROS degrader Mezigdomide was developed and has greatly enhanced IKAROS protein degradation. In this study we show that Mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to Lenalidomide and Iberdomide. Further, we demonstrate that Mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with Menin inhibitors. We show that the superior activity of Mezigdomide compared to Lenalidomide or Iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent Mezigdomide was efficacious in five patient derived xenograft (PDX) models of KMT2A-r and one NPM1c AML. The combination of Mezigdomide with a Menin inhibitor increased survival and prevented the development of recently described MEN1 mutations. These results support prioritization of Mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors.

2024-02-15 | PXD041735 | Pride

Mezigdomide is effective alone and in combination with Menin inhibition in Acute Myeloid Leukemia

2024-02-15 | PXD041737 | Pride

IKAROS and MENIN are Functionally Cooperative Therapeutic Targets in Acute Myeloid Leukemia [ChIP-seq]

Project description:Using ChIP-seq we examined the chromatin occupancy of IKAROS, MENIN, MLL1 and MEIS1 in the MOLM13 and MV4;11 human MLL-fusion acute myeloid leukemia cell lines.

2022-03-10 | GSE168461 | GEO

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