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Molecular targets for therapy

Mutations associated with age-related clonal hematopoiesis in PMF patients with rapid progression to myelofibrosis

Leukemia volume 34, pages 1364–1372 (2020)Cite this article

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Abstract

Besides histopathological findings there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPN). Age-related clonal hematopoiesis (ARCH/CHIP) is a frequent finding in the elderly and combinations with MPN driver mutations (JAK2, MPL, and CALR) have been described. To determine the impact of ARCH/CHIP-related mutations for development of fibrosis in primary myelofibrosis (PMF), the mutational status of cases with fibrotic progression from grade 0 to grade 2/3 (n = 77) as evidenced by follow-up bone marrow biopsies (median 6.2 years) was compared with prefibrotic PMF samples without development of fibrosis (n = 27; median follow-up 7.3 years). Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, and DNMT3A) demonstrable at presentation were not connected with fibrotic progression. However, mutations which are rarely found in ARCH/CHIP (SRSF2, U2AF1, SF3B1, IDH1/2, and EZH2) were present in 24.7% of cases with later development of fibrosis and not detectable in cases staying free from fibrosis (P = 0.0028). Determination of the tumor mutational burden (TMB) in a subgroup of cases (n = 32) did not show significant differences (7.68 mutations/MB vs. 6.85 mutations/MB). We conclude that mutations rarely found in ARCH/CHIP provide an independent risk factor for rapid fibrotic progression (median 2.0 years) when manifest already at first presentation.

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Authors and Affiliations

  1. Institute of Pathology, Hannover Medical School, Carl-Neuberg Str. 1, 30623, Hannover, Germany

    Stephan Bartels, Muhammad Faisal, Guntram Büsche, Jerome Schlue, Britta Hasemeier, Elisa Schipper, Julia Vogtmann, Lina Westphal, Ulrich Lehmann & Hans Kreipe

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  1. Stephan Bartels
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  2. Muhammad Faisal
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  3. Guntram Büsche
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  4. Jerome Schlue
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  5. Britta Hasemeier
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  6. Elisa Schipper
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  7. Julia Vogtmann
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  8. Lina Westphal
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  9. Ulrich Lehmann
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  10. Hans Kreipe
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Contributions

SB, UL, and HK planned the study, interpreted data, and wrote the paper; SB, MF, BH, ES, JV, and LW performed experiments and analyzed the data; GB, JS, and HK contributed the histopathological diagnosis of the patient samples.

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Correspondence to Stephan Bartels.

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Bartels, S., Faisal, M., Büsche, G. et al. Mutations associated with age-related clonal hematopoiesis in PMF patients with rapid progression to myelofibrosis. Leukemia 34, 1364–1372 (2020). https://doi.org/10.1038/s41375-019-0668-5

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