A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias.
A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias.
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作者：
在未成熟的急性髓系和T淋巴恶性肿瘤患者中发现了致白血病的CALM-AF 10融合蛋白。CALM-AF 10白血病显示异常的H3 K79甲基化和增加的HOXA簇基因转录。HOXA基因的表达升高对于白血病的维持和进展至关重要;然而，CALM-AF 10改变HOXA基因表达的确切机制尚不清楚。我们先前确定CALM包含CRM 1依赖的核输出信号（内斯），其对于CALM-AF 10介导的白血病发生是必要且充分的。在这里，我们发现，CALM-AF 10与核输出受体CRM 1的相互作用是激活HOXA基因表达所必需的。我们发现CRM 1定位于HOXA位点，在那里它招募CALM-AF 10，导致HOXA基因的转录和表观遗传激活。CALM-CRM 1相互作用的遗传和药理学抑制阻止了CALM-AF 10在HOXA染色质上的富集，导致转录的立即丧失。这些结果提供了一个全面的机制，通过该机制，CALM-AF 10易位激活关键HOXA簇基因。此外，本报告确定了CRM 1的一个新功能：结合染色质和招募含NES的CALM-AF 10转录因子的能力。
The leukemogenic CALM-AF10 fusion protein is found in patients with immature acute myeloid and T-lymphoid malignancies. CALM-AF10 leukemias display abnormal H3K79 methylation and increased HOXA cluster gene transcription. Elevated expression of HOXA genes is critical for leukemia maintenance and progression; however, the precise mechanism by which CALM-AF10 alters HOXA gene expression is unclear. We previously determined that CALM contains a CRM1-dependent nuclear export signal (NES), which is both necessary and sufficient for CALM-AF10-mediated leukemogenesis. Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression. We show that CRM1 localizes to HOXA loci where it recruits CALM-AF10, leading to transcriptional and epigenetic activation of HOXA genes. Genetic and pharmacological inhibition of the CALM-CRM1 interaction prevents CALM-AF10 enrichment at HOXA chromatin, resulting in immediate loss of transcription. These results provide a comprehensive mechanism by which the CALM-AF10 translocation activates the critical HOXA cluster genes. Furthermore, this report identifies a novel function of CRM1: the ability to bind chromatin and recruit the NES-containing CALM-AF10 transcription factor.
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影响因子：
64.5
作者：
Fornerod, M;Ohno, M;Mattaj, IW
通讯作者：
Mattaj, IW
影响因子：
11.4
作者：
Etchin, J.;Sun, Q.;Kentsis, A.;Farmer, A.;Zhang, Z. C.;Sanda, T.;Mansour, M. R.;Barcelo, C.;McCauley, D.;Kauffman, M.;Shacham, S.;Christie, A. L.;Kung, A. L.;Rodig, S. J.;Chook, Y. M.;Look, A. T.
通讯作者：
Look, A. T.
影响因子：
50.3
作者：
Muntean AG;Tan J;Sitwala K;Huang Y;Bronstein J;Connelly JA;Basrur V;Elenitoba-Johnson KS;Hess JL
通讯作者：
Hess JL
影响因子：
11.4
作者：
Bohlander, SK;Muschinsky, V;Dreyling, MH
通讯作者：
Dreyling, MH
DOI：
10.1073/pnas.93.10.4804
发表时间：
1996-05-14
影响因子：
11.1
作者：
Dreyling, MH;MartinezCliment, JA;Bohlander, SK
通讯作者：
Bohlander, SK