AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors
AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors
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DOI：
10.1182/blood-2010-12-326710
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发表时间：
2011-12-15
期刊：
影响因子：
20.3
通讯作者：
Kurokawa, Mineo
中科院分区：
文献类型：
--
作者：
Nakagawa, Masahiro;Shimabe, Munetake;Kurokawa, Mineo
在许多类型的肿瘤中已经发现转录因子的功能失调。转录因子AML 1/RUNX 1是人类白血病中染色体异常的最常见靶点之一，并且AML 1的功能改变与造血细胞的恶性转化密切相关。然而，AML 1相关白血病的分子基础和治疗靶点仍然是难以捉摸的。在此，我们通过体外同步灭活造血细胞来探索AML 1的直接靶向途径。我们发现AML 1通过与胞浆中I κ B激酶复合物相互作用抑制NF-κ B信号传导。值得注意的是，在髓系肿瘤中发现的AML 1突变体缺乏抑制NF-κ B信号传导的能力，并且患有AML 1相关白血病的人类病例表现出明显活化的NF-κ B信号传导。此外，在具有突变的AML 1的白血病细胞中抑制NF-κ B信号传导有效地阻断它们的生长和白血病的发展。这些发现揭示了AML 1作为NF-κ B信号传导的细胞质衰减剂的新作用，并表明NF-κ B信号传导是AML 1异常的血液恶性肿瘤的有希望的治疗靶点之一。（血。2011;118（25）：6626-6637）
Functional deregulation of transcription factors has been found in many types of tumors. Transcription factor AML1/RUNX1 is one of the most frequent targets of chromosomal abnormalities in human leukemia and altered function of AML1 is closely associated with malignant transformation of hematopoietic cells. However, the molecular basis and therapeutic targets of AML1-related leukemia are still elusive. Here, we explored immediate tar-get pathways of AML1 by in vitro synchronous inactivation in hematopoietic cells. We found that AML1 inhibits NF-kappa B signaling through interaction with I kappa B kinase complex in the cytoplasm. Remarkably, AML1 mutants found in myeloid tumors lack the ability to inhibit NF-kappa B signaling, and human cases with AML1-related leukemia exhibits distinctly activated NF-kappa B signaling. Furthermore, inhibition of NF-kappa B signaling in leukemic cells with mutated AML1 efficiently blocks their growth and development of leukemia. These findings reveal a novel role for AML1 as a cytoplasmic attenuator of NF-kappa B signaling and indicate that NF-kappa B signaling is one of the promising therapeutic targets of hematologic malignancies with AML1 abnormality. (Blood. 2011;118(25):6626-6637)