Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms.
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.
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA; Department of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
Chantana
C
Polprasert
Department of Hematology and Oncology, University of Halle, Halle 06108, Germany; Department of Hematology and Oncology, University of Muenster, Muenster 48149, Germany.
Isabell
I
Schulze
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.
Mikkael A
MA
Sekeres
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Hideki
H
Makishima
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Bartlomiej
B
Przychodzen
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.
Naoko
N
Hosono
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Jarnail
J
Singh
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Richard A
RA
Padgett
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Xiaorong
X
Gu
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
James G
JG
Phillips
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Michael
M
Clemente
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Yvonne
Y
Parker
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Daniel
D
Lindner
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Brittney
B
Dienes
Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
Eckhard
E
Jankowsky
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Yogen
Y
Saunthararajah
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Yang
Y
Du
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Kevin
K
Oakley
Department of Pediatrics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
Nhu
N
Nguyen
Leukemia Program, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH 44195, USA.
Sudipto
S
Mukherjee
Department of Hematology and Oncology, University of Halle, Halle 06108, Germany.
Caroline
C
Pabst
Department of Medicine, Comprehensive Cancer Center and Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL 60637, USA.
Lucy A
LA
Godley
Department of Medicine, Comprehensive Cancer Center and Center for Clinical Cancer Genetics, University of Chicago, Chicago, IL 60637, USA.
Jane E
JE
Churpek
University of Colorado School of Medicine and University of Colorado Cancer Center, Aurora, CO 80045, USA.
Daniel A
DA
Pollyea
Department of Hematology and Oncology, University of Muenster, Muenster 48149, Germany.
Utz
U
Krug
Department of Hematology and Oncology, University of Muenster, Muenster 48149, Germany.
Wolfgang E
WE
Berdel
Institute of Medical Informatics, University of Muenster, Muenster 48149, Germany.
Hans-Ulrich
HU
Klein
Institute of Medical Informatics, University of Muenster, Muenster 48149, Germany.
Martin
M
Dugas
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 113-8654, Japan.
Yuichi
Y
Shiraishi
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 113-8654, Japan.
Kenichi
K
Chiba
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 113-8654, Japan.
Hiroko
H
Tanaka
Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 113-8654, Japan.
Satoru
S
Miyano
Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan.
Kenichi
K
Yoshida
Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan.
Seishi
S
Ogawa
Department of Hematology and Oncology, University of Halle, Halle 06108, Germany; Department of Hematology and Oncology, University of Muenster, Muenster 48149, Germany. Electronic address: carsten.mueller-tidow@uk-halle.de.
Carsten
C
Müller-Tidow
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: maciejj@ccf.org.
Jaroslaw P
JP
Maciejewski
D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D012326:RNA Splicing; D017386:Sequence Homology, Amino Acid
C501226:DDX41 protein, human; D053487:DEAD-box RNA Helicases