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

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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.