Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia
Meningioma 1 is indispensable for mixed lineage leukemia-rearranged acute myeloid leukemia
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DOI：
10.3324/haematol.2018.211201
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发表时间：
2019-08
期刊：
影响因子：
10.1
通讯作者：
Amit Sharma;N. Jyotsana;R. Gabdoulline;D. Heckl;F. Kuchenbauer;R. Slany;A. Ganser;M. Heuser
中科院分区：
文献类型：
--
作者：
Amit Sharma;N. Jyotsana;R. Gabdoulline;D. Heckl;F. Kuchenbauer;R. Slany;A. Ganser;M. Heuser
混合系白血病（MLL/KMT 2A）重排（MLL-r）是急性髓系白血病中最常见的染色体畸变之一。我们通过CRISPR-Cas9介导的MN 1缺失评估了脑膜瘤1（MN 1）（HOXA 9和MEIS 1的辅因子）在人类和小鼠ML重排白血病中的功能。MN 1是MLL阳性鼠和人白血病细胞体内致白血病所必需的。MN 1基因的缺失抑制细胞周期和增殖，促进细胞凋亡，诱导MLL重排细胞分化。表达分析和染色质免疫沉淀与测序从以前报道的数据集表明，MN 1主要保持活跃的转录HOXA 9和HOXA 10，这是关键的下游基因的MLL，和他们的靶基因，如BCL 2，MCL 1和Survivin。与正常的CD 34+造血祖细胞相比，用抗MN 1 siRNA处理ML重排的原代白血病细胞显著降低了它们的克隆形成潜力，这表明MN 1靶向的治疗窗口。总之，我们的研究结果表明，MN 1在MLL融合白血病中起着至关重要的作用，并作为MLL重排的急性髓细胞白血病的治疗靶点。
Mixed lineage leukemia (MLL/KMT2A) rearrangements (MLL-r) are one of the most frequent chromosomal aberrations in acute myeloid leukemia. We evaluated the function of Meningioma 1 (MN1), a co-factor of HOXA9 and MEIS1, in human and murine MLL-rearranged leukemia by CRISPR-Cas9 mediated deletion of MN1. MN1 was required for in vivo leukemogenicity of MLL positive murine and human leukemia cells. Loss of MN1 inhibited cell cycle and proliferation, promoted apoptosis and induced differentiation of MLL-rearranged cells. Expression analysis and chromatin immunoprecipitation with sequencing from previously reported data sets demonstrated that MN1 primarily maintains active transcription of HOXA9 and HOXA10, which are critical downstream genes of MLL, and their target genes like BCL2, MCL1 and Survivin. Treatment of MLL-rearranged primary leukemia cells with anti-MN1 siRNA significantly reduced their clonogenic potential in contrast to normal CD34+ hematopoietic progenitor cells, suggesting a therapeutic window for MN1 targeting. In summary, our findings demonstrate that MN1 plays an essential role in MLL fusion leukemias and serve as a therapeutic target in MLL-rearranged acute myeloid leukemia.