DHX15 and Acute Myeloid Leukemia

The RNA helicase DHX15 (HGNC:2738) has emerged as a significant player in the pathogenesis of acute myeloid leukemia (AML) (MONDO_0018874), with recurrent somatic variants identified in pediatric and adult AML cohorts. In a pediatric study, 20 de novo AML cases underwent genomic profiling that uncovered recurrent mutations in a panel of driver genes including DHX15 (PMID:26941285). This initial evidence set the stage for further investigation into the role of DHX15 in leukemogenesis.

Follow‐up multi‐patient studies have reinforced these findings. An international analysis comprising 331 patients with t(8;21) AML confirmed the presence of recurrent mutations in DHX15 among other genes (PMID:30610028), while an additional mutatome study in 292 patients further underscored its clinical relevance (PMID:31896782). These studies collectively suggest that DHX15 mutations are not isolated events but part of a broader, recurrent mutational landscape in AML.

Genetic evidence is bolstered by the observation that variants in DHX15 typically occur at high variant allele fractions, implying that they mark dominant leukemic clones. Although a canonical HGVS variant string for DHX15 is not explicitly detailed in the literature provided, the consistency of its recurrent alteration across independent studies reinforces its pathogenic role in AML.

Functional studies further substantiate the association by demonstrating that DHX15, a homolog of the yeast splicing factor Prp43, is essential for proper spliceosome disassembly. Investigations using yeast complementation models and ATPase assays have shown that DHX15 can restore growth defects associated with spliceosomal dysfunction (PMID:9342318; PMID:11886864). These functional insights argue that impaired RNA splicing may be a key mechanism through which DHX15 mutations contribute to AML.

The convergence of evidence from genetic profiling and functional assays provides a coherent narrative in which DHX15-mediated dysregulation of RNA splicing plays a contributory role in AML development. The recurrent nature of these somatic variants in independent cohorts further emphasizes the clinical importance of DHX15.

While additional variants and extended functional studies exist that exceed standard scoring thresholds, the available evidence is sufficient to support a strong association between DHX15 and AML.

Key take‑home sentence: The recurrent dysregulation of DHX15 in AML, combined with its critical role in RNA splicing, makes it a promising candidate for diagnostic stratification and targeted therapeutic intervention.

References

• Cancer research • 2016 • Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse PMID:26941285
• Blood • 2019 • Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients PMID:30610028
• Leukemia • 2020 • The clinical mutatome of core binding factor leukemia PMID:31896782
• Proceedings of the National Academy of Sciences of the United States of America • 1997 • Cloning of mDEAH9, a putative RNA helicase and mammalian homologue of Saccharomyces cerevisiae splicing factor Prp43 PMID:9342318
• The Journal of biological chemistry • 2002 • Prp43 is an essential RNA-dependent ATPase required for release of lariat-intron from the spliceosome PMID:11886864

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