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.
Cells are generally stored at low temperature which slows their cellular metabolism. However, the stress induced by cold shock can lead to cell injury or death. Here, we found that exposing human leukemia HL-60 cells to cold shock followed by rewarming (CS/RW) increased the number of dead cells with remodeled genomic structures in which DNA fibers fully unfold and extrude into extracellular space, similar to neutrophil extracellular traps (NETs). The unfolded DNA was associated with NET marker proteins, such as neutrophil elastase and histone H3, and could trap significant numbers of Escherichia coli. We also found that reactive oxygen species-a requisite for NET generation-accumulated during CS/RW in HL-60 cells. This treatment of HL-60 cells to trigger global DNA structural alterations has not been reported before, and helps to elucidate the mechanisms of human cellular response to cold stress.
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