Implication of deregulated vesicles' traffic in the occurence of acute leukemia

网格蛋白包被的囊泡的形成是细胞内膜运输所必需的，并且由ARF GTP酶触发。我们先前鉴定SMAP 1为ARF GTP酶激活蛋白，我们在小鼠中靶向Smap 1，Smap 1缺陷的成红细胞表现出增强的转铁蛋白内吞作用。此外，Smap 1缺陷损害了从多泡体到溶酶体的内化c-Kit的分选，导致c-KIT的积累，伴随着ERK的活化增强和细胞生长增加。有趣的是，老年Smap 1缺陷小鼠发生与红系-髓系形态发育不良细胞相关的贫血，这是与人类骨髓增生异常综合征（MDS）相似的异常。此外，一些Smap 1缺陷小鼠发展成各种亚型的急性髓性白血病（AML）。总的来说，网格蛋白依赖性膜运输的失调可能参与MDS和随后的AML的发展。

The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking and is triggered by the ARF GTPases. We previously identified SMAP1 as an ARF GTPase-activating protein.We targeted Smap1 in mice and Smap1-deficent erythroblasts exhibited enhanced transferrin endocytosis. In addition, Smap1 deficiency impaired the sorting of internalized c-Kit from multivesicular bodies to lysosomes, resulting in accumulation of c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, the deregulation of clathrin-dependent membrane trafficking is likely involved in the development of MDS and subsequent AML.