Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms PMID: 25920683

ADC Targets in Oncology

2026-04-10

Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms

Cancer Cell. 2015 May 11;27(5):658-70. doi: 10.1016/j.ccell.2015.03.017.

Chantana Polprasert ¹ , Isabell Schulze ² , Mikkael A Sekeres ³ , Hideki Makishima ⁴ , Bartlomiej Przychodzen ⁴ , Naoko Hosono ⁵ , Jarnail Singh ⁶ , Richard A Padgett ⁶ , Xiaorong Gu ⁴ , James G Phillips ⁴ , Michael Clemente ⁴ , Yvonne Parker ⁴ , Daniel Lindner ⁴ , Brittney Dienes ⁴ , Eckhard Jankowsky ⁷ , Yogen Saunthararajah ⁴ , Yang Du ⁸ , Kevin Oakley ⁸ , Nhu Nguyen ⁸ , Sudipto Mukherjee ⁹ , Caroline Pabst ¹⁰ , Lucy A Godley ¹¹ , Jane E Churpek ¹¹ , Daniel A Pollyea ¹² , Utz Krug ¹³ , Wolfgang E Berdel ¹³ , Hans-Ulrich Klein ¹⁴ , Martin Dugas ¹⁴ , Yuichi Shiraishi ¹⁵ , Kenichi Chiba ¹⁵ , Hiroko Tanaka ¹⁵ , Satoru Miyano ¹⁵ , Kenichi Yoshida ¹⁶ , Seishi Ogawa ¹⁶ , Carsten Müller-Tidow ¹⁷ , Jaroslaw P Maciejewski ¹⁸

Affiliations

1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA; Department of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
2. Department of Hematology and Oncology, University of Halle, Halle 06108, Germany; Department of Hematology and Oncology, University of Muenster, Muenster 48149, Germany.
3. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA; Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195, USA.
4. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
5. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA; First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui 910-8507, Japan.
6. Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
7. Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
8. Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
9. Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195, USA.
10. Department of Hematology and Oncology, University of Halle, Halle 06108, Germany.
11. Department of Medicine, Comprehensive Cancer Center and Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL 60637, USA.
12. University of Colorado School of Medicine and University of Colorado Cancer Center, Aurora, CO 80045, USA.
13. Department of Hematology and Oncology, University of Muenster, Muenster 48149, Germany.
14. Institute of Medical Informatics, University of Muenster, Muenster 48149, Germany.
15. Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 113-8654, Japan.
16. Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan.
17. Department of Hematology and Oncology, University of Halle, Halle 06108, Germany; Department of Hematology and Oncology, University of Muenster, Muenster 48149, Germany. Electronic address: [email protected].
18. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA; Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195, USA. Electronic address: [email protected].

Abstract

Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of Other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.