Number and type of TET2 mutations in chronic myelomonocytic leukemia and their clinical relevance

TET2, located on chromosome 4q24, is frequently mutated (~60%) in patients with chronic myelomonocytic leukemia (CMML). TET2 has 11 exons, and variations, especially in exon 3 have been described as a part of age-related clonal hematopoiesis. In a large population-based study (n= 17 182), somatic variations involving DNMT3A, TET2 and ASXL1 were seen in ~ 11% of the population 480 years of age, and in comparison with patients without clonal hematopoiesis, were associated with an increased risk of hematological malignancies (HR11.1) and all-cause mortality (HR-3.7). In CMML, thus far, clonal TET2 mutations in the absence of clonal ASXL1 mutations (ASXL1wt/TET2mt) have been associated with favorable outcomes. The exact mechanism behind this interaction remains to be elucidated, one potential explanation being better responses to hypomethylating agents. In the current larger CMML patient cohort (n= 261), we describe the number and type of TET2 mutations and examine their phenotypic and prognostic effects. Two hundred and sixty one patients with CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for the following genes: TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF and SETBP1, by previously described methods. TET2 (NM_001127208.2) coverage extended from exons 3–11, with frame shift, nonsense and missense variations considered pathogenic. Previously annotated single nucleotide polymorphisms (http//www.hapmap.org) were considered non-pathogenic. The 2008 and 2016 World Health Organization (WHO) criteria were used for CMML diagnosis and classification. Among the 261 study patients, 65% were males and median age was 70 years (range, 28–91). One hundred and fifty four (59%), 64 (25%) and 43 (16%) patients were classified as CMML-0, 1 and 2, respectively. At a median follow-up of 23 months, 174 (67%) deaths and 37 (14%) leukemic transformations were documented. Mutational frequencies included: ASXL1 45%, TET2 43%, SRSF2 40%, NRAS 14%, SETBP1 13%, CBL 10%, JAK2 7%, RUNX1 6%,