Cytogenetic correlates of TET2 mutations in 199 patients with myeloproliferative neoplasms

The Ten-Eleven Translocation (TET) oncogen family members include TET1, TET2, and TET3. The TET1 oncogene was first identified as a fusion partner to mixed-lineage leukemia (MLL) gene during the chromosomal translocation t(10;11)(q22;q23) in acute myelogenous leukemia [1,2]. The TET1 gene product catalyzes conversion of 5-methylcytosine to 5-hydroxy-methylcytosine, suggesting a role in epigenetic regulation [3]. TET3 is located at chromosome 2p13.1 and its function is unknown. TET2 is a putative tumor suppressor gene located at chromosome 4q24. Delhommeau et al. first reported the occurrence of TET2 mutations in patients with JAK2V617F-positive MPN [4]. Subsequently, our group reported similar mutations in MPN with and without JAK2V617F mutations, systemic mastocytosis, and other myeloid malignancies [5–8]. In this study, we looked for possible correlations between TET2 mutations and cytogenetic abnormalities in MPN. This study was approved by the institutional review board. Inclusion criteria included availability of bone marrow cytogenetic results at diagnosis or at the time of blood sample collection for TET2 mutation analysis. Follow-up cytogenetic data, where available, were also recorded. The specific MPN diagnosis was established on the basis of the 2001 World Health Organization (WHO) criteria [9]. Both direct techniques and unstimulated culture methods were used to harvest metaphases for analysis from bone marrow aspirate [10]. JAK2V617F mutation analysis was performed according to previously published methods [11]. Cytogenetic findings were assigned as being favorable (sole 20q-, 13q-, or +9), normal, unfavorable (complex or +8), or “other cytogenetic abnormalities”, based on recent prognostic studies in PMF [12,13]. High-throughput DNA sequence analysis was used to screen for TET2 mutations in bone marrow-derived DNA as described previously [5]. A total of 199 MPN patients had information on both TET2 mutational status and karyotype: 71 PV, 43 ET, 55 PMF, 13 post-PV MF, 7 post-ET MF, and 10 with blast phase MPN. Overall, 48 (24%) patients exhibited an abnormal karyotype: 15 favorable, 8 unfavorable, and 25 “others”. TET2 mutations were identified in 25 (13%) patients. As reported before, patients who harbored TET2 mutations were significantly older (P = 0.001) than those with wild-type TET2. In contrast, the distribution of gender, specific MPN diagnosis, and JAK2V617F mutational status was similar between the two groups (Table I). A similar number of patients, 7 (18%) and 41 (24%) with mutated and wild-type TET2, respectively, harbored an abnormal karyotype (P = 0.6). The distribution of cytogenetic categories (favorable, normal, unfavorable or “others”) was also similar between the 2 groups (Tables I and ​andII).II). Similar observations were made when the results of follow-up cytogenetic studies that were available in 79 patients were analyzed (Table I). We conclude that TET2 mutations do not affect initial or subsequent cytogenetic findings in MPN. TABLE I Clinical and Cytogenetic Features at Diagnosis and During Follow-Up in Patients with Myeloproliferative Neoplasms Who Underwent TET2 Mutation Analysis TABLE II Cytogenetic Findings in 25 TET2-Mutated Patients with Myeloproliferative Neoplasms