NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-10-29 DOI:10.1016/j.celrep.2024.114901

Emily B Heikamp, Cynthia Martucci, Jill A Henrich, Dana S Neel, Sanisha Mahendra-Rajah, Hannah Rice, Daniela V Wenge, Florian Perner, Yanhe Wen, Charlie Hatton, Scott A Armstrong

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引用次数: 0

Abstract

Control of stem cell-associated genes by Trithorax group (TrxG) and Polycomb group (PcG) proteins is frequently misregulated in cancer. In leukemia, oncogenic fusion proteins hijack the TrxG homolog KMT2A and disrupt PcG activity to maintain pro-leukemogenic gene expression, though the mechanisms by which oncofusion proteins antagonize PcG proteins remain unclear. Here, we define the relationship between NUP98 oncofusion proteins and the non-canonical polycomb repressive complex 1.1 (PRC1.1) in leukemia using Menin-KMT2A inhibitors and targeted degradation of NUP98 fusion proteins. Eviction of the NUP98 fusion-Menin-KMT2A complex from chromatin is not sufficient to silence pro-leukemogenic genes. In the absence of PRC1.1, key oncogenes remain transcriptionally active. Transition to a repressed chromatin state requires the accumulation of PRC1.1 and repressive histone modifications. We show that PRC1.1 loss leads to resistance to small-molecule Menin-KMT2A inhibitors in vivo. Therefore, a critical function of oncofusion proteins that hijack Menin-KMT2A activity is antagonizing repressive chromatin complexes.

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NUP98 融合蛋白和 KMT2A-MENIN 可拮抗 PRC1.1，从而驱动 AML 中的基因表达。

在癌症中，Trithorax组（TrxG）和Polycomb组（PcG）蛋白对干细胞相关基因的控制经常被误调。在白血病中，致癌融合蛋白会劫持TrxG同源物KMT2A，破坏PcG活性以维持促白血病基因的表达，但融合蛋白拮抗PcG蛋白的机制仍不清楚。在这里，我们利用 Menin-KMT2A 抑制剂和 NUP98 融合蛋白的靶向降解，确定了白血病中 NUP98 oncofusion 蛋白与非经典多聚核抑制复合体 1.1（PRC1.1）之间的关系。将 NUP98 融合蛋白-Menin-KMT2A 复合物从染色质中清除并不足以抑制促白血病基因。在缺乏 PRC1.1 的情况下，关键致癌基因仍具有转录活性。向抑制性染色质状态的转变需要 PRC1.1 的积累和抑制性组蛋白修饰。我们发现，PRC1.1 的缺失会导致体内对小分子 Menin-KMT2A 抑制剂产生抗性。因此，劫持Menin-KMT2A活性的融合蛋白的一个关键功能是拮抗抑制性染色质复合物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.