Genomic breakpoints and clinical features of MLL-TET1 rearrangement in acute leukemias

Recent rapid developments in new technology such as whole genome/exome sequencing have revealed that novel mutations in genes such as DNMT3A, IDH1, IDH2 and TET2 contribute to the main process of leukemogenesis in patients with normal karyotype acute myeloid leukemia (AML).1 Among these genes, TET2, a TET family gene located on 4q24, is important because of its high frequency of mutations in myeloid neoplasms such as myeloproliferative neoplasm (MPN), myelodysplastic syndromes (MDS), MDS/MPN, and AML.2 In contrast, the TET1 gene, first discovered in 2002 and located on 10q22, is rarely reported as a translocation partner for MLL rearrangements in acute leukemias.3,4 Only 10 cases have been reported with chromosomal translocations t(10;11)(q22;q23) interchangeable with MLL-TET1 fusions.4-11 There has been little research into the common features of MLL-TET1 rearrangements. Here we provide information about molecular and clinical characterization of MLL-TET1 rearrangements diagnosed in 3 AML patients.

Using the long-distance inverse-polymerase chain reaction (LDI-PCR) method, 3 AML patients with MLL-TET1 rearrangements were identified between January 2005 and December 2011 at the Diagnostic Center of Acute Leukemia (DCAL) in Frankfurt. All 3 cases were sent to the DCAL because of positive results for MLL rearrangements by conventional cytogenetics and fluorescence in situ hybridization (FISH), but routine analysis did not reveal the fusion partner of MLL. The 3 patients were from different institutions in Korea, Germany and France. Case 2 of this study was briefly mentioned (for rearrangement type) in a previous study.12

The results of clinical parameters, cytogenetic studies, FISH, reverse transcriptase-PCR and LDI-PCR analyses on bone marrow specimens at the time of diagnosis for 3 new AML cases are shown in Table 1. Including 3 new cases, this research analyzes a total of the 13 acute leukemia cases of t(10;11)(q22;q23) known so far, detected in 11 AML and 2 ALL patients. We summarized the published data to evaluate patients' characteristics (Table 2).4-11 A molecular characterization at the genomic or transcript level was performed only for a subset of patients. Eight of 11 AML patients (72.7%) were classified as FAB-M4/M5 subtypes; 7 men and 5 women with a median age of 38.0 years (range 1 month to 67 years). For one patient, no clinical data could be retrieved.11 Of 9 patients with available chromosome study results, 3 had a sole chromosomal abnormality of t(10;11), and the remaining 6 had accompanying additional chromosomal abnormalities. MLL-TET1 rearrangement was confirmed in 8 of 13 cases and chromosomal breakpoints were also identified in these cases (Tables 1 and 2). All genomic breakpoints within the TET1 gene were identified in an approximately 17 kb genomic region flanked by TET1 exons 8 and 12 (Figure 1). But most characterized breakpoints (5 of 7 cases) were mapped to intron 8. Because only 7 of the 13 patients had available clinical outcomes, a sufficient amount of data is not available. Nevertheless, the results showed that 6 patients had complete remission. Five patients, including one who did not reach complete remission, died at an average of 14.5 months after initial diagnosis, showing little difference with the known poor prognosis of patients with MLL rearrangements.

Table 1.Characterization of 3 new acute myeloid leukemia cases with MLL-TET1 gene rearrangement.

Table 2.Summary of previously reported t(10;11) (q22;q23) cases.

Figure 1.Schematic representation of TET1 intron breakpoints on 4 reported cases and 3 new cases using genomic analyses.

TET1 encodes a protein of 2136 amino acids with a molecular mass of 235.3 kDa. TET1 contains a CXXC domain at position 583–624, a coiled-coil region near the C-terminus (position 2,062–2,091), and three candidate bipartite nuclear localization signals.4,7 Lorsbach et al.7 found that the expression of TET1 within the hematolymphoid system was limited to spleen, with no detectable expression in bone marrow or peripheral blood leukocytes. MLL-TET1 fusion proteins are predicted to have a molecular mass of 204.4 kDa and to retain the AT hooks, subnuclear localization domains, and CXXC motif of MLL, as well as the coiled-coil region and the most C-terminal nuclear localization domain of TET1.7 The role of the MLL-TET1 fusion gene in leukemogenesis is unknown, as is the physiological role of TET1.5 Further clinical and molecular research on acute leukemias with MLL-TET1 rearrangements is necessary, including functional study of the MLL-TET1 fusion gene, to define the role of such rare MLL-related fusion genes in leukemogenesis.

There is a need to collect and report recurrent genomic or cytogenetic aberrations since such data on leukemia patients with particular genetic abnormalities improve our current understanding of genetic and clinical features in acute leukemias. Further research on the biological and prognostic effects of MLL-TET1 rearrangements using animal models or human leukemia samples is also required in the near future.