RRC ID 53212
Author Kadono M, Kanai A, Nagamachi A, Shinriki S, Kawata J, Iwato K, Kyo T, Oshima K, Yokoyama A, Kawamura T, Nagase R, Inoue D, Kitamura T, Inaba T, Ichinohe T, Matsui H.
Title Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.
Journal Exp Hematol
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.
Volume 44(8)
Pages 745-754.e4
Published 2016-8-1
DOI 10.1016/j.exphem.2016.04.017
PII S0301-472X(16)30125-4
PMID 27174803
MeSH Aged Aged, 80 and over Amino Acid Substitution Animals Biomarkers Bone Marrow Transplantation Chromosome Aberrations Codon DEAD-box RNA Helicases / genetics* DEAD-box RNA Helicases / metabolism DNA Mutational Analysis Disease Models, Animal Female Gene Expression Genetic Predisposition to Disease* Hematopoietic Stem Cells / metabolism Humans Leukemia, Myeloid, Acute / diagnosis Leukemia, Myeloid, Acute / genetics* Leukemia, Myeloid, Acute / metabolism Male Mice Middle Aged Mutation* Protein Binding Protein Transport
IF 2.82
Times Cited 10
Cord blood stem cells for research