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ACUTE MYELOID LEUKEMIA

Discriminating activities of DEAD-Box Helicase 41 from myeloid malignancy-associated germline variants by genetic rescue

Leukemia volume 37, pages 235–239 (2023)Cite this article

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Heterozygous DEAD-box helicase 41 (DDX41) germline variants generate a predisposition for the development of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Patients present with cytopenias, bone marrow hypocellularity, erythroid dysplasia and/or myeloid malignancy [1]. Although DDX41 is implicated in oncogenic and innate immune mechanisms, there are many unanswered questions about how the ever-increasing spectrum of genetic variants impact DDX41 activity. Assays to discriminate DDX41 variants of undetermined significance from pathogenic variants, which is fundamental for clinical genetic curation, have not been reported, thus limiting the clinical utility of genetic information. Here, we describe a facile genetic rescue assay that discriminates activities of DDX41 from those of human myeloid malignancy-associated germline and somatic DDX41 mutants.

DDX41, a highly conserved member of the RNA helicase family of metazoan proteins [2], exerts post-transcriptional and translational functions, including the regulation of pre-mRNA splicing and ribosomal RNA transcription [3]. DDX41 senses intracellular DNA in the cGAS-STING pathway [4], maintains genomic stability at transcriptional loci harboring R-loops [5] regulates inflammatory gene expression [4] and controls snoRNA processing in mouse leukemic stem/progenitor cells [6].

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Fig. 1: Family histories and structural predictions of myeloid malignancy-associated DDX41 variants.
Fig. 2: Quantitative genetic rescue assay discriminates DDX41 and human myeloid malignancy-associated variant activities.

Data availability

The RNA-seq dataset generated and analyzed during the current study is available in the GEO repository (accession ID: GEO208400). Other data are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by Edward P. Evans Foundation grant, NIH DK68634 and NIH P30CA014520.

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Authors and Affiliations

  1. Wisconsin Blood Cancer Research Institute, Department of Cell and Regenerative Biology, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Jeong-Ah Kim, Daniel R. Matson & Emery H. Bresnick

  2. Department of Biostatistics and Biomedical Informatics, Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Siqi Shen & Sunduz Keles

  3. Division of Hematology, Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Lauren N. Lovrien & Jane E. Churpek

  4. Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    Kelcy J. Smith-Simmer

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  1. Jeong-Ah Kim
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Contributions

JK and EHB designed the study and wrote the manuscripts with input from the other authors. JK and JEC performed experiments and analyzed data. DRM facilitated antibody generation. SS and SK conducted statistical and computational analyses of RNA-seq data. JEC, LL, and KSS were responsible for patient identification and consent and clinical data collection and analysis.

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Correspondence to Jane E. Churpek or Emery H. Bresnick.

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Kim, JA., Shen, S., Matson, D.R. et al. Discriminating activities of DEAD-Box Helicase 41 from myeloid malignancy-associated germline variants by genetic rescue. Leukemia 37, 235–239 (2023). https://doi.org/10.1038/s41375-022-01753-4

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