Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms.
Chromosomal abnormalities are frequent in myeloid malignancies, but in most cases of myelodysplasia (MDS) and myeloproliferative neoplasms (MPN), underlying pathogenic molecular lesions are unknown. We identified recurrent areas of somatic copy number-neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in a large cohort of patients with myeloid malignancies including MDS and related mixed MDS/MPN syndromes using single nucleotide polymorphism arrays. We then investigated genes in the commonly affected area for mutations. When we sequenced TET2, we found homozygous and hemizygous mutations. Heterozygous and compound heterozygous mutations were found in patients with similar clinical phenotypes without LOH4q24. Clinical analysis showed most TET2 mutations were present in patients with MDS/MPN (58%), including CMML (6/17) or sAML (32%) evolved from MDS/MPN and typical MDS (10%), suggesting they may play a ubiquitous role in malignant evolution. TET2 mutations affected conserved domains and the N terminus. TET2 is widely expressed in hematopoietic cells but its function is unknown, and it lacks homology to other known genes. The frequency of mutations in this candidate myeloid regulatory gene suggests an important role in the pathogenesis of poor prognosis MDS/MPN and sAML and may act as a disease gene marker for these often cytogenetically normal disorders.
Jankowska
Anna M
AM
Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, OH 44195, USA.
Szpurka
Hadrian
H
Tiu
Ramon V
RV
Makishima
Hideki
H
Afable
Manuel
M
Huh
Jungwon
J
O'Keefe
Christine L
CL
Ganetzky
Rebecca
R
McDevitt
Michael A
MA
Maciejewski
Jaroslaw P
JP
D000208:Acute Disease; D000328:Adult; D000595:Amino Acid Sequence; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics* / Q000648:ultrastructure; D015331:Cohort Studies; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D049308:Dioxygenases; D018450:Disease Progression; D005838:Genotype; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D053208:Kaplan-Meier Estimate; D007951:Leukemia, Myeloid / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human; D053614:Janus Kinase 2