Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia

Somatic TET2 mutations (TET2 ^MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). TET2 ^MT includes mostly loss-of-function/hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic TET2 gene inactivations (biTET2 ) in CMML. We speculated that biTET2 might be associated with distinct clinicohematological features. We analyzed TET2 ^MT in 1045 patients with MN. Of 82 biTET2 cases, 66 were biTET2 ^MT, 13 were hemizygous TET2 ^MT, and 3 were homozygous TET2 ^MT (uniparental disomy); the remaining patients (denoted biTET2 hereafter) were either monoallelic TET2 ^MT (n = 96) or wild-type TET2 (n = 823). Truncation mutations were found in 83% of biTET2 vs 65% of biTET2 cases (P = .02). TET2 hits were founder lesions in 72% of biTET2 vs 38% of biTET2 cases (P < .0001). In biTET2 , significantly concurrent hits included SRSF2 ^MT (33%; P < .0001) and KRAS/NRAS ^MT (16%; P = .03) as compared with biTET2 When the first TET2 hit was ancestral in biTET2 , the most common subsequent hits affected a second TET2 ^MT, followed by SRSF2 ^MT, ASXL1 ^MT, RAS ^MT, and DNMT3A ^MT BiTET2 patients without any monocytosis showed an absence of SRSF2 ^MT BiTET2 patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with biTET2 patients. Hence, while a second TET2 hit occurred frequently, biTET2 did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2 showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2 might represent an auxiliary assessment tool in MN.