TET2 Mutations Revealed by Whole Genome Sequencing in Adult T-Cell Leukemia.

Abstract 2697

Adult T cell leukemia (ATL) is an aggressive peripheral T-cell neoplasm highly resistant to conventional therapies. The development of ATL is thought to be initiated by immortalization of T cells by human T cell leukemia virus type I (HTLV-I) infection in early childhood, followed by accumulating genetic hits during a long latency period, which eventually cause neoplastic transformation of T-cells. However, little has been known about those genetic hits that are involved in the pathogenesis of ATL, except for the role of tax protein in T-cell immortalization and alterations of other genes, including TP53, p16 and TCF8.

So, in order to understand the genetic basis of ATL, we performed whole genome sequencing of paired-normal DNA from an ATL patient. In total 77 non-silent somatic mutations were detected, among which a TET2 mutation (R1261C) immediately drew our attention. TET2 mutations are found in a wide variety of myeloid malignancies in high frequency and implicated in their pathogenesis. The TET families of proteins are thought to be involved in the epigenetic regulation of gene expression through catalyzing conversion of 5'-methyl cytosine to 5'-hydroxymethyl cytosine, which are supposed to be further converted to unmethylated cytosine. One of the recent interests in TET2 mutations was the recent report of frequent TET2 mutations in peripheral T cell neoplasms, including angioimmunoblastic T-cell lymphomas, peripheral T-cell lymphomas not otherwise specified, as well as other B cell neoplasms, which is in agreement with the observation in TET2-deficient mice, which showed an expansion of bone marrow progenitor pools involving immature lymphoid populations, indicating that deregulated epigenetic machineries could be also involved in the development of mature lymphoid neoplasms.

To explore this hypothesis, 144 samples of ATL were screened for mutations in TET2 and other epigenetic regulators commonly mutated in myeloid malignancies, including DNMT3A, IDH1/2 and spliceosome genes, using target deep sequencing. We found 16 TET2 mutations in 13 out of the 144 ATL cases (9%) together with other mutations, which was similar to the frequencies reported in other peripheral T cell neoplasms. Deep sequencing allowed for accurate estimation of allelic burden of these mutations. In most cases, TET2 mutations were found in the major tumor populations, indicating their early origin during clonal evolution. In addition, DNMT3A (2%), IDH1/2 (1%), SF3B1 (2%), ZRSR2 (1%) were also mutated, although at lower frequencies.

In conclusion, we found TET2 mutation through whole genome sequencing. TET2 mutations were relatively common in ATL. Together with other mutations frequently found in myeloid malignancies, our finding provided an intriguing insight into the role of deregulated DNA methylation in the pathogenesis of ATL and also suggested that a common mechanism may underlie between the two very different blood cancers.