title: Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7.
abstract: 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 in vivo 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.
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nagamachi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsui
authors.forename: Hiroya
authors.initials: H
authors.lastname: Asou
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ozaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aki
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D011992:Endosomes / Q000378:metabolism / Q000473:pathology; D023061:Gene Order; D018390:Gene Targeting; D057895:Haploinsufficiency; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007942:Leukemia, Experimental; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D051379:Mice; D018345:Mice, Knockout; D008979:Moloney murine leukemia virus / Q000472:pathogenicity; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012192:Retroviridae Infections / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics*; D014412:Tumor Virus Infections / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C514443:SAMD9 protein, human; C560581:Samd9L protein, mouse; D025521:Tumor Suppressor Proteins