Loss-of-Function TET2 Mutations: Adding Fire to Hematologic Malignancies?

By Josef T. Prchal, MD

2009-09-01

Dr. Prchal indicated no relevant conflicts of interest.

Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289-301.

Langemeijer SM, Kuiper RP, Berends M, et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet. 2009;41:838-42.

Saint-Martin C, Leroy G, Delhommeau F, et al. Analysis of the Ten-Eleven Translocation (TET)2 gene in familial myeloproliferative neoplasms. Blood. 2009. [Epub ahead of print]

Somatic mutations in JAK2 in Philadelphia-chromosome-negative (Ph-) myeloproliferative disorders (MPD), FLT 3 and other genes in acute myelocytic leukemias (AML), and numerous others reported in myelodysplastic syndromes (MDS) are clearly not sufficient to explain the full genesis of these disorders. Thus, the recent finding of a multitude of mutations of the tumor suppressive gene TET2 in numerous malignant hematologic entities has created a lot of excitement.

TET2 is a homolog of the gene originally discovered at the chromosome Ten-Eleven Translocation (TET) site in a subset of patients with acute leukemia. TET2 was first found in AML patients with deletions of chromosome 4q24 and was suggested to be a tumor suppressor gene. Delhommeau and colleagues, from a group headed by Drs. Bernard and Vainchenker in France, reported at the 2008 ASH Annual Meeting and now in the New England Journal of Medicine that mutations and deletions in this gene were found in bone marrow cells from a significant proportion of patients with Ph- MPD (both JAK2V617F positive and negative), AML, and MDS. The TET2 gene spans 150 kb and has 11 exons, and since mutations are distributed throughout the entire gene, their delineation was a formidable task. They demonstrated that the TET2 loss-of-function mutations originate in pluripotent hematopoietic stem cells but seem to favor myeloid rather than lymphoid proliferation, and that in many patients both alleles were affected. In the five patients with MPD who also had the JAK2V617F mutation, elegant in vitro studies coupled with transplantation of hematopoietic stem cells into immuno-deficient mice demonstrated that TET2 mutations preceded the JAK2V617F mutation.

An independent study of MDS patients by Langemeijer and colleagues, from Jensen’s group in the Netherlands, also submitted for publication in 2008, reached similar conclusions. Using Single Nulcleotide Polymorphism (SNP) microarrays, they analyzed 102 MDS patients for copy number alterations and loss of heterozygosity. Approximately one-quarter of the patients had abnormalties at the TET2 locus. In most patients with large deletions at the 4q24 TET2 locus, mutations were also present in the non-deleted allele. Interestingly, the burden of the second mutant TET2 allele was more variable, suggesting that mutations are acquired sequentially with the progression of disease and that multiple clones may exist in the same individual. One of the studied subjects later progressed to AML, and in the leukemic blasts, the 4q24 deletion and the nonsense TET2 mutation were retained. This is quite different from leukemic transformation of JAK2V617F-positive MPDs, where transformed leukemic cells are generally negative for JAK2 mutations.

These papers were followed by others from additional groups who confirmed the findings and showed that TET2 mutations are also seen in systemic mastocytosis1 and chronic myelomonocytic leukemia,2 and that the frequency of TET2 mutations in MPD increases with age but does not alter the disease severity.3 These studies raise the important question of whether the TET2 mutation could be the pre-JAK2V617F somatic event responsible for MPDs.

An important study published online in Blood from Saint-Martin and colleagues from the French Group of Familial Myeloproliferative Disorders led by Bellanne-Chantelot demonstrated conclusively by studying families with multiple cases of MPD that TET2 mutations cannot be disease-initiating, as the mutations differ among affected relatives. Further, they found that in some instances the TET2 mutations followed, rather than preceded, the appearance of the JAK2V617F mutation. Their work also suggests that the TET2 mutations can increase the risk of transformation to myelofibrosis, contrary to what was reported in a study by a group from the Mayo Clinic.

As to the mechanism of TET2 leukemia-promoting activity, Mullighan, in an editorial in Nature Genetics, postulated a possible mechanism. A related family member, TET1, catalyzes the conversion of 5-methylcytosine in DNA to 5-hydroxymethylcytosine, suggesting a potential role for TET proteins in epigenetic regulation.4 However, mutations of two related genes, TET1 and TET3, have not yet been reported.5 Clearly more remains to be learned about the function of TET2 and other family members of the TET gene group.

  1. Tefferi A, Levine RL, Lim KH, et al. Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009;23:900-4.
  2. Jankowska AM, Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009 Jun 18;113(25):6403-10
  3. Tefferi A, Pardanani A, Lim KH, et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia. 2009;23:905-11.
  4. Mullighan CG. TET2 mutations in myelodysplasia and myeloid malignancies. Nat Genet. 2009;41:766-7
  5. Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood. 2009;114:144-47.

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