Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia
| Autor: | Daichi Inoue, Satoru Shinriki, Takeshi Kawamura, Akiko Nagamachi, Toshio Kitamura, Tatsuo Ichinohe, Toshiya Inaba, Akinori Kanai, Koji Iwato, Taiichi Kyo, Moe Kadono, Kumi Oshima, Akihiko Yokoyama, Jin Kawata, Hirotaka Matsui, Reina Nagase |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Cancer Research Myeloid DNA Mutational Analysis Mutant Gene Expression Biology medicine.disease_cause DEAD-box RNA Helicases Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Humans Genetic Predisposition to Disease Codon Molecular Biology Aged Bone Marrow Transplantation Suppressor mutation Aged 80 and over Chromosome Aberrations Mutation Myeloid leukemia Cell Biology Hematology Middle Aged Hematopoietic Stem Cells RNA Helicase A Molecular biology Disease Models Animal Leukemia Myeloid Acute Protein Transport Haematopoiesis 030104 developmental biology MRNA Sequencing medicine.anatomical_structure Amino Acid Substitution 030220 oncology & carcinogenesis Cancer research Female Biomarkers Protein Binding |
| Zdroj: | Experimental Hematology. 44:745-754.e4 |
| ISSN: | 0301-472X |
| DOI: | 10.1016/j.exphem.2016.04.017 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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