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Mutational landscape of chronic myelomonocytic leukemia and its potential clinical significance

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Abstract

We evaluated the mutational landscape of chronic myelomonocytic leukemia (CMML) and its potential clinical significance. We analyzed 47 samples with a panel of 112 genes using next-generation sequencing. Forty-five of the 47 patients (95.74%) had at least one mutation identified, with an average of 3.7 (range 0–9) per patient. The most common mutation was NRAS, followed by ASXL1, TET2, SRSF2, RUNX1, KRAS, and SETBP1. Patients 60 years and older more frequently had mutations in TET2 (56% vs. 9.09%, P = 0.001) and ASXL1 (48% vs. 18.18%, P = 0.031) than patients younger than 60 years. Median overall survival (OS) in patients with CMML was 22.0 months (95% CI 19.7–24.3 months). ASXL1 (18 vs. 22 months, P = 0.012), RUNX1 (17 vs. 22 months, P = 0.001), and SETBP1 (20 vs. 27 months, P = 0.032) mutations predicted inferior OS. However, only RUNX1 mutation was significantly associated with inferior acute myeloid leukemia (AML)-free survival. Our data showed that mutation profile differed significantly between CMML patients aged 60 years and older versus those younger than 60 years, and some of these mutations impact the progression and prognosis of the disease to a certain extent.

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References

  1. Bacher U, Haferlach T, Schnittger S, Kreipe H, Kröger N. Recent advances in diagnosis, molecular pathology and therapy of chronic myelomonocytic leukaemia. Br J Haematol. 2011;153(2):149–67.

    Article  PubMed  Google Scholar 

  2. Patnaik MM, Parikh SA, Hanson CA, Tefferi A. Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review. Br J Haematol. 2014;165(3):273–86.

    Article  PubMed  Google Scholar 

  3. Itzykson R, Duchmann M, Lucas N, Solary E. CMML: clinical and molecular aspects. Int J Hematol. 2017;105(6):711–9.

    Article  PubMed  Google Scholar 

  4. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.

    Article  CAS  PubMed  Google Scholar 

  5. Patel AB, Deininger MW. Genetic complexity of chronic myelomonocytic leukemia. Leuk Lymphoma. 2020;18:1–22.

    Google Scholar 

  6. Muramatsu H, Makishima H, Maciejewski JP. Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: novel pathogenetic lesions. Semin Oncol. 2012;39(1):67–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ma L, Jiang L, Yang W, Luo Y, Mei C, Zhou X, et al. Real-world data of chronic myelomonocytic leukemia: a Chinese single-center retrospective study. Cancer Med. 2021;10(5):1715–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Germing U, Kündgen A, Gattermann N. Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma. 2004;45(7):1311–8.

    Article  CAS  PubMed  Google Scholar 

  9. Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31(19):2428–36.

    Article  CAS  PubMed  Google Scholar 

  10. Padron E, Garcia-Manero G, Patnaik MM, Itzykson R, Lasho T, Nazha A, et al. An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J. 2015;5(7):e333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jian JL, Qiao YH, Zhang SL, Ma HZ, Liu B. Comparison of existing prognostic models in chronic myelomonocytic leukemia. Chin Med J (Engl). 2020;133(4):496–8.

    Article  Google Scholar 

  12. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K, et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood. 2011;118(14):3824–31.

    Article  CAS  PubMed  Google Scholar 

  14. Costa R, Abdulhaq H, Haq B, Shadduck RK, Latsko J, Zenati M, et al. Activity of azacitidine in chronic myelomonocytic leukemia. Cancer. 2011;117(12):2690–6.

    Article  CAS  PubMed  Google Scholar 

  15. Cheng H, Kirtani VG, Gergis U. Current status of allogeneic HST for chronic myelomonocytic leukemia. Bone Marrow Transpl. 2012;47(4):535–41.

    Article  CAS  Google Scholar 

  16. Patnaik MM, Vallapureddy R, Yalniz FF, Hanson CA, Ketterling RP, Lasho TL, et al. Therapy related-chronic myelomonocytic leukemia (CMML): molecular, cytogenetic, and clinical distinctions from de novo CMML. Am J Hematol. 2018;93(1):65–73.

    Article  CAS  PubMed  Google Scholar 

  17. Mangaonkar AA, Patnaik MM. Advances in chronic myelomonocytic leukemia and future prospects: Lessons learned from precision genomics. Adv Cell Gene Ther. 2019;2(2):e48.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management. Am J Hematol. 2020;95(1):97–115.

    Article  CAS  PubMed  Google Scholar 

  19. Hwang SM, Kim SM, Nam Y, Kim J, Kim S, Ahn YO, et al. Targeted sequencing aids in identifying clonality in chronic myelomonocytic leukemia. Leuk Res. 2019;84:106190.

    Article  CAS  PubMed  Google Scholar 

  20. Jiang Z, Sun X, Wu Z, Alhatem A, Zheng R, Liu D, et al. Cytogenetic and molecular landscape and its potential clinical significance in Hispanic CMML patients from Puerto Rico. Oncotarget. 2020;11(47):4411–20.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Patnaik MM, Tefferi A. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia. Blood Cancer J. 2016;6(2):e393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. McCarthy C. ISCN 2005: an international system for human cytogenetic nomenclature [book review]. Melbourne: Australian Institute of Medical Scientists; 2006.

    Google Scholar 

  23. Such E, Cervera J, Costa D, Solé F, Vallespí T, Luño E, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica. 2011;96(3):375–83.

    Article  PubMed  Google Scholar 

  24. Lin LI, Chen CY, Lin DT, Tsay W, Tang JL, Yeh YC, et al. Characterization of CEBPA mutations in acute myeloid leukemia: most patients with CEBPA mutations have biallelic mutations and show a distinct immunophenotype of the leukemic cells. Clin Cancer Res. 2005;11(4):1372–9.

    Article  CAS  PubMed  Google Scholar 

  25. Chen W, Konoplev S, Medeiros LJ, Koeppen H, Leventaki V, Vadhan-Raj S, et al. Cuplike nuclei (prominent nuclear invaginations) in acute myeloid leukemia are highly associated with FLT3 internal tandem duplication and NPM1 mutation. Cancer. 2009;115(23):5481–9.

    Article  CAS  PubMed  Google Scholar 

  26. Chao H, Zhou M, Zhang R. A case with ZNF198-FGFR1 gene rearrangement presenting as acute eosinophil myeloid leukemia. Chin Med J (Engl). 2015;128(1):131–2.

    Article  Google Scholar 

  27. Wang K, Zhou F, Cai X, Chao H, Zhang R, Chen S. Mutational landscape of patients with acute myeloid leukemia or myelodysplastic syndromes in the context of RUNX1 mutation. Hematology. 2020;25(1):211–8.

    Article  CAS  PubMed  Google Scholar 

  28. Coltro G, Patnaik MM. Chronic myelomonocytic leukemia: insights into biology, prognostic factors, and treatment. Curr Oncol Rep. 2019;21(11):101.

    Article  PubMed  Google Scholar 

  29. Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28(2):241–7.

    Article  CAS  PubMed  Google Scholar 

  30. Lin PH, Li HY, Fan SC, Yuan TH, Chen M, Hsu YH, et al. A targeted next-generation sequencing in the molecular risk stratification of adult acute myeloid leukemia: implications for clinical practice. Cancer Med. 2017;6(2):349–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yang J, Yao DM, Ma JC, Yang L, Guo H, Wen XM, et al. The prognostic implication of SRSF2 mutations in Chinese patients with acute myeloid leukemia. Tumour Biol. 2016;37(8):10107–14.

    Article  CAS  PubMed  Google Scholar 

  32. Li B, Mascarenhas JO, Rampal RK. Leukemic transformation of myeloproliferative neoplasms: therapeutic and genomic considerations. Curr Hematol Malig Rep. 2018;13(6):588–95.

    Article  PubMed  Google Scholar 

  33. Meggendorfer M, Roller A, Haferlach T, Eder C, Dicker F, Grossmann V, et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood. 2012;120(15):3080–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Patel BJ, Przychodzen B, Thota S, Radivoyevitch T, Visconte V, Kuzmanovic T, et al. Genomic determinants of chronic myelomonocytic leukemia. Leukemia. 2017;31(12):2815–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Elena C, Gallì A, Such E, Meggendorfer M, Germing U, Rizzo E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128(10):1408–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ricci C, Fermo E, Corti S, Molteni M, Faricciotti A, Cortelezzi A, et al. RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant. Clin Cancer Res. 2010;16(8):2246–56.

    Article  CAS  PubMed  Google Scholar 

  37. Cui Y, Tong H, Du X, Li B, Gale RP, Qin T, et al. TET2 mutations were predictive of inferior prognosis in the presence of ASXL1mutations in patients with chronic myelomonocytic leukemia. Stem Cell Investig. 2016;23(3):50.

    Article  Google Scholar 

  38. Mason CC, Khorashad JS, Tantravahi SK, Kelley TW, Zabriskie MS, Yan D, et al. Age-related mutations and chronic myelomonocytic leukemia. Leukemia. 2016;30(4):906–13.

    Article  CAS  PubMed  Google Scholar 

  39. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Coltro G, Mangaonkar AA, Lasho TL, Finke CM, Pophali P, Carr R, 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. 2020;34(5):1407–21.

    Article  CAS  PubMed  Google Scholar 

  41. Patnaik MM, Lasho TL, Finke CM, Hanson CA, Hodnefield JM, Knudson RA, et al. Spliceosome mutations involving SRSF2, SF3B1, and U2AF35 in chronic myelomonocytic leukemia: prevalence, clinical correlates, and prognostic relevance. Am J Hematol. 2013;88(3):201–6.

    Article  CAS  PubMed  Google Scholar 

  42. Patnaik MM, Lasho TL, Vijayvargiya P, Finke CM, Hanson CA, Ketterling RP, et al. Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia. Blood Cancer J. 2016;6(1):e385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kuo MC, Liang DC, Huang CF, Shih YS, Wu JH, Lin TL, et al. RUNX1 mutations are frequent in chronic myelomonocytic leukemia and mutations at the C-terminal region might predict acute myeloid leukemia transformation. Leukemia. 2009;23(8):1426–31.

    Article  CAS  PubMed  Google Scholar 

  44. Amer MZ, Xin H, Jessica BL, Rong W, Xiaomei M, Nikolai AP, et al. Hypomethylating agent therapy use and survival in older patients with chronic myelomonocytic leukemia in the United States: a large population-based study. Cancer. 2017;123(19):3754–62.

    Article  Google Scholar 

  45. Geissler K, Jäger E, Barna A, et al. Correlation of RAS-Pathway Mutations and Spontaneous Myeloid Colony Growth with Progression and Transformation in Chronic Myelomonocytic Leukemia-A Retrospective Analysis in 337 Patients. Int J Mol Sci. 2020;21(8):3025.

  46. Véronique GB, Virginie T, Julien R, José A, Nadine C, Benjamin E, et al. ASXL1 mutation is associated with poor prognosis and acute transformation in chronic myelomonocytic leukaemia. Br J Haematol. 2010;151(4):365–75.

    Article  Google Scholar 

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Acknowledgements

The authors thank all the physicians who provided leukemia samples and clinical data.

Funding

This work was partly supported by Grants from Young Scientists Foundation of Changzhou No. 2 People's Hospital (No. 2019K002), Science and Technology Project of Changzhou Health Committee (No. QN202035), Science and Technology Development Fund project of Nanjing Medical University (No. NMUB201), Major Science Project of Changzhou Health Commission (ZD202018). Project of science and technology support for social development, Science and Technology Bureau of Changzhou (CE20205027).

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  1. Wenmin Han and Feng Zhou contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Affiliated Changzhou Second Hospital of Nanjing Medical University, Changzhou, 213003, China

    Wenmin Han, Feng Zhou, Wei Qin, Zhuxia Jia, Xiaohui Cai, Meiyu Chen, Jie Liu, Hongying Chao & Xuzhang Lu

  2. Department of Hematology, The First Affiliated Hospital of Soochow University, Soochow, 215000, China

    Zheng Wang

  3. SuZhou Jsuniwell Medical Laboratory, Suzhou, 214000, China

    Zheng Wang

  4. Department of Hematology, Wuxi Third People’s Hospital, Wuxi, 214000, China

    Haiying Hua

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  1. Wenmin Han
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Han, W., Zhou, F., Wang, Z. et al. Mutational landscape of chronic myelomonocytic leukemia and its potential clinical significance. Int J Hematol 115, 21–32 (2022). https://doi.org/10.1007/s12185-021-03210-x

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