Department of Pediatric Oncology, Dana-Farber Cancer Institute, and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02215, USA.
Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Cell Rep. 2024 Nov 26;43(11):114901. doi: 10.1016/j.celrep.2024.114901. Epub 2024 Oct 30.
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.
转录激活因子复合物相关基因（TrxG）和多梳抑制复合物（PcG）蛋白对干细胞相关基因的控制在癌症中经常失调。在白血病中，致癌融合蛋白劫持 TrxG 同源物 KMT2A 并破坏 PcG 活性，以维持促白血病基因的表达，尽管致癌融合蛋白拮抗 PcG 蛋白的机制仍不清楚。在这里，我们使用 Menin-KMT2A 抑制剂和靶向降解 NUP98 融合蛋白，定义了白血病中 NUP98 癌融合蛋白与非典型多梳抑制复合物 1.1（PRC1.1）之间的关系。将 NUP98 融合-Menin-KMT2A 复合物从染色质上逐出不足以沉默促白血病基因。在没有 PRC1.1 的情况下，关键的癌基因仍然具有转录活性。向受抑制的染色质状态的转变需要 PRC1.1 和抑制性组蛋白修饰的积累。我们表明，PRC1.1 的缺失导致体内对小分子 Menin-KMT2A 抑制剂的耐药性。因此，劫持 Menin-KMT2A 活性的癌融合蛋白的一个关键功能是拮抗抑制性染色质复合物。
