4.6 Article

Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia

期刊

BLOOD ADVANCES
卷 3, 期 3, 页码 339-349

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AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2018024216

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资金

  1. National Institutes of Health, National Heart, Lung, and Blood Institute [R01HL118281, R01HL123904, R01HL132071, R35HL135795]
  2. Edward P. Evans Foundation

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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 TET2MT (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/NRASMT (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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