2009.06.18 – Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms


Blood, 18 June 2009, Vol. 113, No. 25, pp. 6403-6410.
Prepublished online as a Blood First Edition Paper on April 16, 2009; DOI 10.1182/blood-2009-02-205690.


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

Anna M. Jankowska1, Hadrian Szpurka1, Ramon V. Tiu1,2, Hideki Makishima1, Manuel Afable2, Jungwon Huh1,3, Christine L. O’Keefe1, Rebecca Ganetzky1, Michael A. McDevitt4, and Jaroslaw P. Maciejewski1,2

1 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, and 2 Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic, OH; 3 Department of Laboratory Medicine, School of Medicine, Ewha Womans University, Seoul, South Korea; and 4 Divisions of Hematology and Hematological Malignancy, Departments of Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD

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.