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Spotlight on Clonal Evolution in Leukemias

An evolutionary perspective on chronic myelomonocytic leukemia

Leukemia volume 27, pages 1441–1450 (2013)Cite this article

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Abstract

Chronic myelomonocytic leukemia (CMML) shares with other myeloid diseases a number of somatic gene mutations. These mutations can now be integrated within the framework of evolution theory to address the mechanisms of the disease. Several evidences indicate that the disease emerges in adult hematopoietic stem cells (HSC) through the age-dependent accumulation of DNA damage, leading stochastically to a driver mutation that confers a competitive advantage to the cell. A mutation in TET2 gene could be one of these driver mutations provoking the emergence of clonality. After a long latency, secondary lesions, such as mutations in the SRSF2 gene, contribute to progression to full-blown malignancy, with abnormal differentiation. Additional mutations accumulate and branching arising mostly through mitotic recombination generates clonal heterogeneity. Modifications in the microenvironment probably affect this clonal dynamics, whereas epigenetic alterations, such as hypermethylation of the TIF1γ gene promoter, may generate phenotypic diversification of otherwise clonal populations. The preserved although deregulated myeloid differentiation that characterizes CMML, with granulomonocyte expansion and various cytopenias, may depend on early clonal dominance in the hematopietic cell hierarchy. Progression to acute myeloid leukemia observed in 25–30% of the patients may arise from the massive expansion of a clone with novel genetic lesions, providing a high fitness to previously minor subclones when in chronic phase of the disease. This review discusses the various models of disease emergence and progression and how this recent knowledge could drive rational therapeutic strategies.

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Acknowledgements

We are indebted to William Vainchenker and Olivier Bernard for insightful discussions. We apologize to several other authors contributing to the field of myeloid neoplasms or clonal evolution of cancer whose work could not be cited due to space restrictions. This research is supported by grants from the Ligue Nationale Contre le Cancer (Label, ES), and the French National Cancer Institute (PHRC 2011 to ES and support to RI). UMR1009 is supported by the ARC Foundation and the Région Ile-de-France.

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  1. Department of Hematology, Inserm UMR1009, Institut Gustave Roussy, Villejuif, France

    R Itzykson & E Solary

  2. IFR54, Institut Gustave Roussy, Villejuif, France

    R Itzykson & E Solary

  3. Faculty of Medicine, University Paris-Sud 11, Le Kremlin-Bicêtre, France

    R Itzykson & E Solary

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  1. R Itzykson
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  2. E Solary
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Correspondence to E Solary.

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Itzykson, R., Solary, E. An evolutionary perspective on chronic myelomonocytic leukemia. Leukemia 27, 1441–1450 (2013). https://doi.org/10.1038/leu.2013.100

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  • DOI: https://doi.org/10.1038/leu.2013.100

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