title: RUNX1/AML1 mutant collaborates with BMI1 overexpression in the development of human and murine myelodysplastic syndromes.
abstract: RUNX1/AML1 mutations have been identified in myelodysplastic syndromes (MDSs). In a mouse bone marrow transplantation model, a RUNX1 mutant, D171N, was shown to collaborate with Evi1 in the development of MDSs; however, this is rare in humans. Using enforced expression in human CD34(+) cells, we showed that the D171N mutant, the most frequent target of mutation in the RUNX1 gene, had an increased self-renewal capacity, blocked differentiation, dysplasia in all 3 lineages, and tendency for immaturity, but no proliferation ability. BMI1 overexpression was observed in CD34(+) cells from the majority of MDS patients with RUNX1 mutations, but not in D171N-transduced human CD34(+) cells. Cotransduction of D171N and BMI1 demonstrated that BMI1 overexpression conferred proliferation ability to D171N-transduced cells in both human CD34(+) cells and a mouse bone marrow transplantation model. Stepwise transduction of D171N followed by BMI1 in human CD34(+) cells resulted in long-term proliferation with a retained CD34(+) cell fraction, which is quite similar to the phenotype in patients with higher-risk MDSs. Our results indicate that BMI1 overexpression is one of the second hit partner genes of RUNX1 mutations that contribute to the development of MDSs.
authors.affiliation: Division of Radiation Information Registry, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Harada
authors.forename: Daichi
authors.initials: D
authors.lastname: Inoue
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.forename: Jun
authors.initials: J
authors.lastname: Imagawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Doki
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Yahata
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
authors.forename: Goro
authors.initials: G
authors.lastname: Sashida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
mesh_terms: D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018952:Antigens, CD34; C069077:BMI1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D012333:RNA, Messenger; C493728:RUNX1 protein, human; D063150:Polycomb Repressive Complex 1