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CALM 中的核输出信号对于 CALM-AF10 诱导的白血病是必需的。

Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia.

机构信息

Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.

出版信息

Cancer Sci. 2014 Mar;105(3):315-23. doi: 10.1111/cas.12347. Epub 2014 Feb 13.

DOI:10.1111/cas.12347
PMID:24397609
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4317939/
Abstract

The CALM-AF10 fusion gene, which results from a t(10;11) translocation, is found in a variety of hematopoietic malignancies. Certain HOXA cluster genes and MEIS1 genes are upregulated in patients and mouse models that express CALM-AF10. Wild-type clathrin assembly lymphoid myeloid leukemia protein (CALM) primarily localizes in a diffuse pattern within the cytoplasm, whereas AF10 localizes in the nucleus; however, it is not clear where CALM-AF10 acts to induce leukemia. To investigate the influence of localization on leukemogenesis involving CALM-AF10, we determined the nuclear export signal (NES) within CALM that is necessary and sufficient for cytoplasmic localization of CALM-AF10. Mutations in the NES eliminated the capacity of CALM-AF10 to immortalize murine bone-marrow cells in vitro and to promote development of acute myeloid leukemia in mouse models. Furthermore, a fusion of AF10 with the minimal NES can immortalize bone-marrow cells and induce leukemia in mice. These results suggest that during leukemogenesis, CALM-AF10 plays its critical roles in the cytoplasm.

摘要

CALM-AF10 融合基因源于 t(10;11)易位，存在于多种血液恶性肿瘤中。在表达 CALM-AF10 的患者和小鼠模型中，某些 HOXA 簇基因和 MEIS1 基因被上调。野生型网格蛋白组装淋巴髓性白血病蛋白（CALM）主要在细胞质中呈弥散模式定位，而 AF10 则在核内定位；然而，CALM-AF10 在哪里发挥作用诱导白血病尚不清楚。为了研究定位对涉及 CALM-AF10 的白血病发生的影响，我们确定了 CALM 中的核输出信号（NES），该信号对于 CALM-AF10 的细胞质定位是必要和充分的。NES 中的突变消除了 CALM-AF10 在体外使鼠骨髓细胞永生化和促进小鼠急性髓性白血病发展的能力。此外，AF10 与最小 NES 的融合可以使骨髓细胞永生化并在小鼠中诱导白血病。这些结果表明，在白血病发生过程中，CALM-AF10 在细胞质中发挥关键作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/16192ad2345a/cas0105-0315-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/f23a24a6fec4/cas0105-0315-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/5561d340e9f6/cas0105-0315-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/18e1a2f34eee/cas0105-0315-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/9223f3a91cb0/cas0105-0315-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/16192ad2345a/cas0105-0315-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/f23a24a6fec4/cas0105-0315-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/5561d340e9f6/cas0105-0315-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/18e1a2f34eee/cas0105-0315-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/9223f3a91cb0/cas0105-0315-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5f6/4317939/16192ad2345a/cas0105-0315-f5.jpg

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