Somatic mutations in TET2 are common in myelodysplastic syndromes (MDS), myeloproliferative, and overlap syndromes. TET2 mutant (TET2MT) clones are also found in asymptomatic elderly individuals, a condition referred to as clonal hematopoiesis of indeterminate potential (CHIP). In various entities of TET2MT neoplasia, we examined the phenotype in relation to the strata of TET2 hits within the clonal hierarchy. Using deep sequencing, 1781 mutations were found in 1205 of 4930 patients; 40% of mutant cases were biallelic. Hierarchical analysis revealed that of TET2MT cases >40% were ancestral, e.g., representing 8% of MDS. Higher (earlier) TET2 lesion rank within the clonal hierarchy (greater clonal burden) was associated with impaired survival. Moreover, MDS driven by ancestral TET2MT is likely derived from TET2MT CHIP with a penetrance of ~1%. Following ancestral TET2 mutations, individual disease course is determined by secondary hits. Using multidimensional analyses, we demonstrate how hits following the TET2 founder defect induces phenotypic shifts toward dysplasia, myeloproliferation, or progression to AML. In summary, TET2MT CHIP-derived MDS is a subclass of MDS that is distinct from de novo disease.
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This work was supported by grants R01HL118281, R01HL123904, R01HL132071, R35HL135795, and Edward P. Evans Foundation.
CMH performed DNA-sequencing experiments, collected/analyzed data, and wrote the manuscript. AN and KK collected data. BPP, MM, YG, and NN performed DNA-sequencing experiments, and analyzed DNA-sequencing data. MAS and TH provided patient samples and clinical data. AG, HA, and MFA provided clinical data. VA, VV, and YN edited the manuscript and advised on experiments. MEA, BKJ, TL, TR, RO, and JPM designed and conceptualized the overall research and wrote the manuscript. All authors read and approved the final manuscript.
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The authors declare that they have no conflict of interest.
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Hirsch, C.M., Nazha, A., Kneen, K. et al. Consequences of mutant TET2 on clonality and subclonal hierarchy. Leukemia 32, 1751–1761 (2018). https://doi.org/10.1038/s41375-018-0150-9
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