2009.03.05 – TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis

http://www.nature.com/leu/journal/v23/n5/abs/leu200947a.html
Original Article
Leukemia (2009) 23, 905–911; doi:10.1038/leu.2009.47; published online 5 March 2009
Chronic Myeloproliferative Neoplasias

TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis

A Tefferi1, A Pardanani1, K-H Lim1,2, O Abdel-Wahab3,4, T L Lasho1, J Patel3, N Gangat1, C M Finke1, S Schwager1, A Mullally5, C-Y Li1, C A Hanson1, R Mesa1, O Bernard6,7,8, F Delhommeau9, W Vainchenker9, D G Gilliland5,10 and R L Levine3,4

Abstract
High-throughput DNA sequence analysis was used to screen for TET2 mutations in bone marrow-derived DNA from 239 patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs). Thirty-two mutations (19 frameshift, 10 nonsense, 3 missense; mostly involving exons 4 and 12) were identified for an overall mutational frequency of 13%. Specific diagnoses included polycythemia vera (PV; n=89), essential thrombocythemia (ET; n=57), primary myelofibrosis (PMF; n=60), post-PV MF (n=14), post-ET MF (n=7) and blast phase PV/ET/MF (n=12); the corresponding mutational frequencies were 16, 5, 17, 14, 14 and 17% (P=0.50). Mutant TET2 was detected in 17 and 7% of JAK2V617F-positive and -negative cases, respectively (P=0.04). However, this apparent clustering of the two mutations was accounted for by an independent association between mutant TET2 and advanced age; mutational frequency was 23% in patients 60 years old versus 4% in younger patients (P<0.0001). The presence of mutant TET2 did not affect survival, leukemic transformation or thrombosis in either PV or PMF; a correlation with hemoglobin <10 g per 100 ml in PMF was noted (P=0.05). We conclude that TET2 mutations occur in both JAK2V617F-positive and -negative MPN, are more prevalent in older patients, display similar frequencies across MPN subcategories and disease stages, and hold limited prognostic relevance.
Keywords:
JAK2, MPL, myeloproliferative, polycythemia, thrombocythemia, myelofibrosis

1Divisions of Hematology and Hematopathology, Departments of Medicine and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA
2Division of Hematology-Oncology, Mackay Memorial Hospital and Mackay Medicine, Nursing and Management College, Taipei, Taiwan
3Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
4Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
5Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
6INSERM E0210, Hopital Necker
7APHP Laboratoire d’Hématologie, Hôpital Cochin
8Université Paris V, Paris, France
9INSERM U790, Institut Gustave Roussy, Villejuif, France
10The Howard Hughes Medical Institute, Boston, MA, USA
Correspondence: Professor A Tefferi, Departments of Medicine and Laboratory Medicine, Divisions of Hematology and Hematopathology, Mayo Clinic, Rochester, MN 55905, USA. E-mail: tefferi.ayalew@mayo.edu; Dr RL Levine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. E-mail: leviner@mskcc.org
Received 3 February 2009; Accepted 6 February 2009; Published online 5 March 2009.