| RRC ID |
53212
|
| 著者 |
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.
|
| タイトル |
Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.
|
| ジャーナル |
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.
|
| 巻・号 |
44(8)
|
| ページ |
745-754.e4
|
| 公開日 |
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
|
| 引用数 |
10
|
| リソース情報 |
| 研究用ヒト臍帯血幹細胞 |
|
