title: Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.
abstract: The DDX41 gene, encoding a DEAD-box type ATP-dependent RNA helicase, is rarely but reproducibly mutated in myeloid diseases. The acquired mutation in DDX41 is highly concentrated at c.G1574A (p.R525H) in the conserved motif VI located at the C-terminus of the helicase core domain where ATP interacts and is hydrolyzed. Therefore, it is likely that the p.R525H mutation perturbs ATPase activity in a dominant-negative manner. In this study, we screened for the DDX41 mutation of CD34-positive tumor cells based on mRNA sequencing and identified the p.R525H mutation in three cases among 23 patients. Intriguingly, these patients commonly exhibited acute myeloid leukemia (AML) with peripheral blood cytopenias and low blast counts, suggesting that the mutation inhibits the growth and differentiation of hematopoietic cells. Data from cord blood cells and leukemia cell lines suggest a role for DDX41 in preribosomal RNA processing, in which the expression of the p.R525H mutant causes a certain ribosomopathy phenotype in hematopoietic cells by suppressing MDM2-mediated RB degradation, thus triggering the inhibition of E2F activity. This study uncovered a pathogenic role of p.R525H DDX41 in the slow growth rate of tumor cells. Age-dependent epigenetic alterations or other somatic changes might collaborate with the mutation to cause AML.
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Kadono
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Kanai
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Nagamachi
authors.affiliation: Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Central Clinical Laboratory, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Shinriki
authors.affiliation: Central Clinical Laboratory, Kumamoto University Hospital, Kumamoto, Japan.
authors.forename: Jin
authors.initials: J
authors.lastname: Kawata
authors.affiliation: Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Iwato
authors.affiliation: Department of Hematology, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan.
authors.forename: Taiichi
authors.initials: T
authors.lastname: Kyo
authors.affiliation: Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Laboratory for Malignancy Control Research, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yokoyama
authors.affiliation: Department of Molecular Biology and Medicine, Laboratory for System Biology and Medicine (LSBM), Research Center for Advanced Science and Technology (RCAST), University of Tokyo, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Reina
authors.initials: R
authors.lastname: Nagase
authors.affiliation: Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Inoue
authors.affiliation: Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. Electronic address: nohe@hiroshima-u.ac.jp.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ichinohe
authors.affiliation: Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Molecular Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Central Clinical Laboratory, Kumamoto University Hospital, Kumamoto, Japan. Electronic address: hmatsui@kumamoto-u.ac.jp.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsui
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D000818:Animals; D015415:Biomarkers; D016026:Bone Marrow Transplantation; D002869:Chromosome Aberrations; D003062:Codon; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport
chemical_list: D015415:Biomarkers; D003062:Codon; C501226:DDX41 protein, human; D053487:DEAD-box RNA Helicases