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 ⁱ ) in CMML. We speculated that biTET2 ⁱ might be associated with distinct clinicohematological features. We analyzed TET2 ^MT in 1045 patients with MN. Of 82 biTET2 ⁱ 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 ⁱ vs 65% of biTET2 ^- cases (P = .02). TET2 hits were founder lesions in 72% of biTET2 ⁱ vs 38% of biTET2 ^- cases (P < .0001). In biTET2 ⁱ , 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 ⁱ , the most common subsequent hits affected a second TET2 ^MT, followed by SRSF2 ^MT, ASXL1 ^MT, RAS ^MT, and DNMT3A ^MT BiTET2 ⁱ patients without any monocytosis showed an absence of SRSF2 ^MT BiTET2 ⁱ 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 ⁱ did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2 ⁱ showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2 ⁱ might represent an auxiliary assessment tool in MN.

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