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

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 9.38). 03/2009; 23(5):905-11. DOI: 10.1038/leu.2009.47
Source: PubMed

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 approximately 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 approximately 16, 5, 17, 14, 14 and 17% (P=0.50). Mutant TET2 was detected in approximately 17 and approximately 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 approximately 23% in patients > or =60 years old versus approximately 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.

Download full-text


Available from: Terra Lasho, Aug 07, 2014
  • Source
    • "In contrast to Tet1, very little is known about the function of Tet2 or Tet3. Although it is highly expressed in the adult cortex, most studies of Tet2 have examined its role in cancer and early development (Delhommeau et al., 2009; Figueroa et al., 2010; Ko et al., 2011; Mullighan, 2009; Tefferi et al., 2009; Xu et al., 2012). These studies reported a correlation between Tet2 and global DNA hypomethylation, and demonstrated that Tet2 knockdown leads to defects in neuronal differentiation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dynamic variations in DNA methylation regulate neuronal gene expression in an experience-dependent manner. Although DNA methylation has been implicated in synaptic plasticity, learning and memory, active DNA demethylation is also induced by learning, which suggests that an interaction between the two processes is necessary for cognitive function. Active DNA demethylation is a complex process involving a variety of proteins and epigenetic regulatory enzymes, the understanding of which with respect to its role in the adult brain is in its infancy. We here provide an overview of the current understanding of active DNA demethylation, and describe how this process may establish persistent epigenetic states that are associated with neural plasticity and memory formation.
    Neurobiology of Learning and Memory 06/2013; 105. DOI:10.1016/j.nlm.2013.06.009 · 4.04 Impact Factor
  • Source
    • "The stable TET2 mutational status from ET to overt AML indicates that loss of TET2 function was not implicated in disease progression in this case but rather represents an early priming event in the hematopoietic progenitors. Presence of multiple TET2 mutations, two loss-of-function and one missense variant, has not been described previously in ET patients [4]. The A1505T might be a rare normal germline variant, but involved tissue was not available for confirmation of this. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic myeloid neoplasms have susceptibility to transform into acute myeloid leukemia due to attainment of additional molecular lesions. We here describe the kinetics of a del(7q) driven leukemogenesis in a patient with multiple TET2 mutations and JAK2 V617F mutated chronic myeloproliferative neoplasm. The del(7q) emerged in the accelerated phase of disease, which was preceded by a lag phase of almost three years with normalized peripheral blood cell counts. Our results reveal that the del(7q), independently of other lesions, acts as a leukemic driver in this patient and that the stable long-lasting normalization of peripheral blood cell values concealed pending transformation.
    01/2013; 2(2):51–53. DOI:10.1016/j.lrr.2013.06.001
  • Source
    • "The presence of activating mutation V617F in Janus kinase 2 (JAK2) gene is a hallmark of MPN, since 97 % of PV patients and about 50 % of ET and PMF patients harbor this mutation (Baxter et al. 2005; James et al. 2005; Kralovics et al. 2005; Levine et al. 2005). Only a small portion of JAK2V617F-negative patients have other mutations , such as JAK2 exon 12 mutations (Scott et al. 2007), MPL exon 10 mutations (Pardanani et al. 2006; Beer et al. 2008), and mutations in CBL (Grand et al. 2009) and TET2 (Tefferi et al. 2009). There is strong evidence that mutations in these genes are decisive events that are responsible for the majority of biological and clinical features of MPN (Plo and Vainchenker 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The expression of Janus kinase 2 (JAK2) gene is altered in myeloproliferative neoplasms (MPN) and the regulation of transcription could be a mechanism that modulates JAK2 gene expression. We analyzed the transcriptional potential of single-nucleotide polymorphism (SNP) rs12343867 T > C in JAK2 intron 14, tagging 46/1 haplotype, and its influence on JAK2 gene expression. Functional analysis of JAK2 intron 14 was performed using the pBLCAT5 reporter system in K562 cells. Identification of the proteins binding to the intron 14 regulatory element was accomplished by electrophoretic mobility shift assay (EMSA) and supershift assays. Quantification of the expression of JAK2 gene in a cohort of 51 MPN patients and 12 healthy controls was performed by real-time quantitative polymerase chain reaction (RQ-PCR). Functional analysis revealed that the intronic DNA element harboring SNP rs12343867 T > C acts as a transcriptional repressor in vitro. The repressor activity was significantly attenuated by the presence of nucleotide C. Supershift analysis showed the enrolment of transcriptional factor Meis1 in this process. RQ-PCR experiments showed increased JAK2 expression in patients with the JAK2V617F mutation, with a significant difference between essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) patients. SNP rs12343867 showed no statistically significant influence on the expression of JAK2 gene in MNP patients.
    Journal of applied genetics 11/2012; 54(1). DOI:10.1007/s13353-012-0125-x · 1.90 Impact Factor
Show more