Haploinsufficiency of SAMD9L, an Endosome Fusion Facilitator, Causes Myeloid Malignancies in Mice Mimicking Human Diseases with Monosomy 7

Monosomy 7 and interstitial deletion of 7q (-7/7q-) are well-recognized nonrandom chromosomal abnormalities frequently found among patients with myelodysplastic syndromes (MDSs) and myeloid leukemias. We previously identified candidate myeloid tumor suppressor genes (SAMD9, SAMD9-like= SAMD9L, and Miki) in the 7q21.3 subband. We established SAMD9L-deficient mice and found that SAMD9L^+/- mice as well as SAMD9L^-/- mice develop myeloid diseases resembling human diseases associated with -7/7q. SAMD9L-deficient hematopoietic stem cells showed enhanced colony formation potential and invivo reconstitution ability. SAMD9L localizes in early endosomes. SAMD9L-deficient cells showed delays in homotypic endosome fusion, resulting in persistence of ligand-bound cytokine receptors. These findings suggest that haploinsufficiency of SAMD9L and/or SAMD9 gene(s) contributes to myeloid transformation.