Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia

Abstract

Somatic <i>TET2</i> mutations (<i>TET2</i> ^MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). <i>TET2</i> ^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 <i>TET2</i> gene inactivations (<i>biTET2</i> ^<i>i</i> ) in CMML. We speculated that <i>biTET2</i> ^<i>i</i> might be associated with distinct clinicohematological features. We analyzed <i>TET2</i> ^MT in 1045 patients with MN. Of 82 <i>biTET2</i> ^<i>i</i> cases, 66 were <i>biTET2</i> ^MT, 13 were hemizygous <i>TET2</i> ^MT, and 3 were homozygous <i>TET2</i> ^MT (uniparental disomy); the remaining patients (denoted <i>biTET2</i> ^<i>-</i> hereafter) were either monoallelic <i>TET2</i> ^MT (n = 96) or wild-type <i>TET2</i> (n = 823). Truncation mutations were found in 83% of <i>biTET2</i> ^<i>i</i> vs 65% of <i>biTET2</i> ^<i>-</i> cases (<i>P</i> = .02). <i>TET2</i> hits were founder lesions in 72% of <i>biTET2</i> ^<i>i</i> vs 38% of <i>biTET2</i> ^<i>-</i> cases (<i>P</i> < .0001). In <i>biTET2</i> ^<i>i</i> , significantly concurrent hits included <i>SRSF2</i> ^MT (33%; <i>P</i> < .0001) and <i>KRAS</i>/<i>NRAS</i> ^MT (16%; <i>P</i> = .03) as compared with <i>biTET2</i> ^<i>-</i> When the first <i>TET2</i> hit was ancestral in <i>biTET2</i> ^<i>i</i> , the most common subsequent hits affected a second <i>TET2</i> ^MT, followed by <i>SRSF2</i> ^MT, <i>ASXL1</i> ^MT, <i>RAS</i> ^MT, and <i>DNMT3A</i> ^MT <i>BiTET2</i> ^<i>i</i> patients without any monocytosis showed an absence of S<i>RSF2</i> ^MT <i>BiTET2</i> ^<i>i</i> patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with <i>biTET2</i> ^<i>-</i> patients. Hence, while a second <i>TET2</i> hit occurred frequently, <i>biTET2</i> ^<i>i</i> did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, <i>biTET2</i> ^<i>i</i> showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, <i>biTET2</i> ^<i>i</i> might represent an auxiliary assessment tool in MN.