Clinical, molecular, and prognostic correlates of number, type, and functional localization of TET2 mutations in chronic myelomonocytic leukemia (CMML)—a study of 1084 patients

Giacomo Coltro, Abhishek A. Mangaonkar, Terra L. Lasho, Christy M. Finke, Prateek Pophali, Ryan Carr, Naseema Gangat, Moritz Binder, Animesh Pardanani, Martin Fernandez-Zapico, Keith D. Robertson, Alberto Bosi, Nathalie Droin, Alessandro M. Vannucchi, Ayalew Tefferi, Anthony Hunter, Eric Padron, Eric Solary, Mrinal M. Patnaik

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Loss-of-function TET2 mutations (TET2MT) are frequent early clonal events in myeloid neoplasms and are thought to confer a fitness advantage to hematopoietic precursors. This large, multi-institutional study (n = 1084), investigated the TET2 mutational landscape and prognostic implications of the number, type, and location of TET2MT and the epistatic relationship with other somatic events in chronic myelomonocytic leukemia (CMML). Nine hundred and forty-two TET2MT were identified in 604 (56%) patients, of which 710 (75%) were predicted to be truncating (involving the catalytic domain). Three hundred and sixteen (29%) patients had ≥1 TET2MT, with 28%, 1%, and 0.2% harboring 2, 3, and 5 mutations, respectively. In comparison to TET2WT, TET2MT patients were older in age, more likely to have dysplastic CMML, a higher number of co-occurring mutations, and lower-risk stratification. Importantly, TET2MT were associated with a survival advantage (49 vs. 30 months, p < 0.0001), especially in the context of multiple TET2MT (≥2; 57 months, p < 0.001), and truncating TET2MT (51 months, p < 0.001). In addition, the adverse prognostic impact of ASXL1MT was partially mitigated by concurrent TET2MT, with the ASXL1WT/TET2MT genotype having better outcomes and resulting in further risk stratification of ASXL1 inclusive CMML prognostic models, in comparison to ASXL1MT alone.

Original languageEnglish (US)
Pages (from-to)1407-1421
Number of pages15
JournalLeukemia
Volume34
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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