Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML Journal Article
| Authors: | Payne, E. M.; Bolli, N.; Rhodes, J.; Abdel-Wahab, O. I.; Levine, R.; Hedvat, C. V.; Stone, R.; Khanna-Gupta, A.; Sun, H.; Kanki, J. P.; Gazda, H. T.; Beggs, A. H.; Cotter, F. E.; Look, A. T. |
| Article Title: | Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML |
| Abstract: | In a zebrafish mutagenesis screen to identify genes essential for myelopoiesis, we identified an insertional allele hi1727, which disrupts the gene encoding RNA helicase dead-box 18 (Ddx18). Homozygous Ddx18 mutant embryos exhibit a profound loss of myeloid and erythroid cells along with cardiovascular abnormalities and reduced size. These mutants also display prominent apoptosis and a G1 cell-cycle arrest. Loss of p53, but not Bcl-xl overexpression, rescues myeloid cells to normal levels, suggesting that the hematopoietic defect is because of p53-dependent G1 cell-cycle arrest. We then sequenced primary samples from 262 patients with myeloid malignancies because genes essential for myelopoiesis are often mutated in human leukemias. We identified 4 nonsynonymous sequence variants (NSVs) of DDX18 in acute myeloid leukemia (AML) patient samples. RNA encoding wild-type DDX18 and 3 NSVs rescued the hematopoietic defect, indicating normal DDX18 activity. RNA encoding one mutation, DDX18-E76del, was unable to rescue hematopoiesis, and resulted in reduced myeloid cell numbers in ddx18hi1727/+ embryos, indicating this NSV likely functions as a dominant- negative allele. These studies demonstrate the use of the zebrafish as a robust in vivo system for assessing the function of genes mutated in AML, which will become increasingly important as more sequence variants are identified by next-generation resequencing technologies. © 2011 by The American Society of Hematology. |
| Keywords: | adult; controlled study; unclassified drug; acute granulocytic leukemia; gene mutation; gene sequence; human cell; major clinical study; nonhuman; mutant protein; animal cell; allele; gene overexpression; apoptosis; cell maturation; embryo; genetic variability; gene function; in vivo study; protein bcl xl; wild type; protein p53; dead box protein; gene disruption; cardiovascular disease; erythroid cell; hematopoietic cell; homozygote; gene loss; hematopoiesis; bone marrow cell; protein p21; genetic code; cell cycle g1 phase; zebra fish; rna helicase dead box 18; myelopoiesis |
| Journal Title: | Blood |
| Volume: | 118 |
| Issue: | 4 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2011-07-28 |
| Start Page: | 903 |
| End Page: | 915 |
| Language: | English |
| DOI: | 10.1182/blood-2010-11-318022 |
| PROVIDER: | scopus |
| PMCID: | PMC3148170 |
| PUBMED: | 21653321 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 3 October 2011" - "CODEN: BLOOA" - "Source: Scopus" |
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