Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms

• Published in: Blood Vol. 113; no. 25; pp. 6403 - 6410
• Main Authors: Jankowska, Anna M., Szpurka, Hadrian, Tiu, Ramon V., Makishima, Hideki, Afable, Manuel, Huh, Jungwon, O'Keefe, Christine L., Ganetzky, Rebecca, McDevitt, Michael A., Maciejewski, Jaroslaw P.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 18-06-2009; Americain Society of Hematology; American Society of Hematology
• Series: Myeloid Neoplasia
• Subjects: Acute Disease; Adult; Amino Acid Sequence; Biological and medical sciences; Chromosomes, Human, Pair 4 - genetics; Chromosomes, Human, Pair 4 - ultrastructure; Cohort Studies; Conserved Sequence; Disease Progression; DNA Mutational Analysis; DNA, Neoplasm - genetics; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Genotype; Hematologic and hematopoietic diseases; Humans; Janus Kinase 2 - genetics; Kaplan-Meier Estimate; Leukemia, Myeloid - genetics; Leukemia, Myelomonocytic, Chronic - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loss of Heterozygosity; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Myelodysplastic Syndromes - genetics; Myeloid Neoplasia; Myeloproliferative Disorders - genetics; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Sequence Alignment; Sequence Homology, Amino Acid; Young Adult; Myeloproliferative syndrome; Allelic imbalance; Hematology; Loss of heterozygosity; Genetics; Hemopathy; Chromosome B4; Mutation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-02-205690

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.