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Myelodysplastic syndrome

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

Leukemia volume 34, pages 1407–1421 (2020)Cite this article

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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.

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Fig. 1: Molecular characteristics, including concurrent gene mutations, mutation type and localization, distribution of multiple mutations and mutational signatures in TET2 mutant pateints with chronic myelomonocytic leukemia.
Fig. 2: Kaplan-Meier survival estimates in patients with CMML, AML, PV, ET, MDS and DLBCL, stratified by the presence or absence of TET2 mutations.
Fig. 3: Kaplan-Meier survial estimates in CMML patients stratified by their ASXL1/TET2 mutational status and the impact of the ASXL1WT/TET2MT genotype on risk stratification using CMML-specific prognostic models.
Fig. 4: Kaplan-Meier survival estimates in patients with CMML stratified by their TET2 mutational status, the ASXL1/TET2 genotype and treatment with hypomethylating agents.

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Acknowledgements

Current publication is supported in part by grants from the “The Henry J. Predolin Foundation for Research in Leukemia”, and the “Gerstner Family Career Development Award”, “Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA”. This work was also partly funded by the Conquer Cancer Foundation of ASCO Young Investigator Award awarded to AAM. Any opinions, findings, and conclusions expressed in this material are those of the authors and do not necessarily reflect those of the American Society of Clinical Oncology or Conquer Cancer Foundation or the funder. AMV was partially supported by grant Accelerator Award from CR, UK and AIRC, I. AMV and GC were supported by AIRC 5 × 1000 call “Metastatic disease: the key unmet need in oncology” to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). ES team is supported by the Ligue Nationale Contre le Cancer (Equipe labellisée Ligue 2017) and grants from Institut National du Cancer (INCa TRANSLA13-157; PRT-K16-057; PRT-K16-067).

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Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Giacomo Coltro, Abhishek A. Mangaonkar, Terra L. Lasho, Christy M. Finke, Prateek Pophali, Ryan Carr, Naseema Gangat, Moritz Binder, Animesh Pardanani, Ayalew Tefferi & Mrinal M. Patnaik

  2. Haematology Unit, AOU Careggi, University of Florence, Florence, Italy

    Giacomo Coltro & Alberto Bosi

  3. CRIMM, Centro di Ricerca e Innovazione per le Malattie Mieloproliferative, AOU Careggi, Florence, Italy

    Giacomo Coltro & Alessandro M. Vannucchi

  4. Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Martin Fernandez-Zapico & Keith D. Robertson

  5. INSERM U1170, Gustave Roussy Cancer Center, 94805, Villejuif, France

    Nathalie Droin & Eric Solary

  6. Faculté de Médecine, Université Paris-Sud, 94270, Le Kremlin-Bicêtre, France

    Nathalie Droin & Eric Solary

  7. INSERM US23, CNRS UMS 3655, AMMICa, Genomic platform, Gustave Roussy Cancer Center, 94805, Villejuif, France

    Nathalie Droin

  8. Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA

    Anthony Hunter & Eric Padron

  9. Department of Hematology, Gustave Roussy Cancer Center, 94805, Villejuif, France

    Eric Solary

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  1. Giacomo Coltro
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Coltro, G., Mangaonkar, A.A., Lasho, T.L. et al. Clinical, molecular, and prognostic correlates of number, type, and functional localization of TET2 mutations in chronic myelomonocytic leukemia (CMML)—a study of 1084 patients. Leukemia 34, 1407–1421 (2020). https://doi.org/10.1038/s41375-019-0690-7

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