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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

Multiple TET2 mutations confer additional survival benefit in both myelodysplastic and myeloproliferative chronic myelomonocytic leukemia subtypes

Leukemia volume 39, pages 2030–2034 (2025)Cite this article

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Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping myelodysplastic (MD) and myeloproliferative (MP) features [1, 2]. Somatic TET2 mutations (TET2MT) are present in 40–60% of CMML patients and are associated with improved overall (OS) and acute leukemia free survival (LFS) [3, 4]. This is due, in part, to a protective effect of TET2MT in the context of adverse ASXL1MT and a higher response rate to hypomethylating agents (HMA) [4, 5]. Approximately 50% of TET2 mutated cases have multiple TET2MT (range 47-52% [4,5,6]) which have been associated with better survival outcomes [4]. As TET2MT are frequent early ancestral events, multi-hit TET2MT are often subclonal and mostly occur in trans, contributing to biallelic TET2 inactivation [7, 8].

CMML is subclassified into MD and MP subtypes based on a white blood cell count of <13 × 109/L for MD-CMML [1]. Although CMML is considered a single disease entity for risk stratification [9,10,11], these subtypes are distinct, with MP-CMML being enriched for RAS-pathway mutations and associated with inferior survival [12]. Whether the survival benefits associated with TET2MT extend to both CMML subtypes is unknown.

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Fig. 1: Landscape of TET2 Mutations in Chronic Myelomonocytic Leukemia (CMML).
Fig. 2: Overall Survival (OS) and Acute Leukemia Free Survival (LFS) of the Primary and External Cohorts by the Number of TET2 Mutations.

Data availability

Data are available upon reasonable request to the corresponding author(s).

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Acknowledgements

This work was supported in part by each participating institution. MMP would like to acknowledge the NCI for R01 grant R01CA272496-03.

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Author notes

  1. These authors contributed equally: Eric Padron, Guillermo Montalban-Bravo, Mrinal M. Patnaik.

Authors and Affiliations

  1. Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, 55905, USA

    Clifford M. Csizmar, Anuya Natu, Mark Gurney, Saubia Fathima, Ali Khalid A. Alsugair, Terra L. Lasho, Christy M. Finke, Aref Al-Kali, Hassan Alkhateeb, Kebede Begna, Naseema Gangat, Mehrdad Hefazi Torghabeh, Aasiya Matin, Abhishek A. Mangaonkar, Antoine N. Saliba, Ayalew Tefferi & Mrinal M. Patnaik

  2. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Rashmi Kanagal-Shamanna & Sanam Loghavi

  3. Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Alexandre Bazinet, Kelly Chien, Danielle Hammond, Courtney DiNardo, Tapan Kadia, Farhad Ravandi-Kashani, Naveen Pemmaraju, Koji Sasaki, Guillermo Garcia-Manero, Hagop M. Kantarjian & Guillermo Montalban-Bravo

  4. Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL, 33612, USA

    Rami S. Komrokji, Zhuoer Xie, Najla A. Ali, David Sallman & Eric Padron

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  1. Clifford M. Csizmar
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Contributions

CMC collected data, performed the analyses, and drafted the manuscript. EP, GMB, and MMP conceived and supervised the study. AN, MG, SF, AKAA, RKS, SL, AB, KC, DH, CD, TK, FRK, NP, KS, TLL, CMF, AK, HA, KB, NG, MHT, AM, AAM, ANS, AT, GGM, HMK, RSK, ZX, NAA, and DS assisted with data collection. All authors reviewed and revised the manuscript.

Corresponding author

Correspondence to Mrinal M. Patnaik.

Ethics declarations

Competing interests

MMP has received research funding from Kura Oncology, Stem Line, Epigenetix, Polaris and has served on the advisory board for CTI pharmaceuticals.

Ethics approval

This retrospective study was approved by the Institutional Review Boards (IRB) at each center. The IRBs deemed this study to be minimal risk and thus exempt from written informed consent.

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Csizmar, C.M., Natu, A., Gurney, M. et al. Multiple TET2 mutations confer additional survival benefit in both myelodysplastic and myeloproliferative chronic myelomonocytic leukemia subtypes. Leukemia 39, 2030–2034 (2025). https://doi.org/10.1038/s41375-025-02648-w

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