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ACUTE MYELOID LEUKEMIA

How fast does leukemia progress?

Leukemia volume 39, pages 805–809 (2025)Cite this article

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Acquisition of somatic mutations in healthy human cells is ubiquitous and age-related, although can increase the risk of cancers and nonmalignant diseases, and of all-cause mortality [1]. Somatic mutagenesis leads to genetically divergent clonal populations and decreased stem cell pool diversity, a process known as clonal hematopoiesis (CH) [2]. Hematopoietic stem cells (HSCs) can acquire 20 somatic mutations/year across the whole genome and 0.1 mutations/year in protein-coding exons. If a mutations provides a selective advantage, HSCs harboring that alteration expand, a phenomenon known as clonal evolution, common with ageing [3]. Clonal evolution is defined as the selection of a particular cancer cell population from tumor heterogeneity and is considered a Darwinian-like model to explain the process by which tumor cells survive through continuous external selection pressures, such as immune surveillance [4]. Currently, the most accepted model is the branched evolution, where a common ancestor gives rise multiple co-existing clones diverging and evolving in parallel with the acquisition of additional mutations. CH is frequent with ageing, in non-hematological conditions (e.g. cardiovascular diseases), and several hematological diseases, including monoclonal gammopathy of uncertain significance. However, its clinical significance remains unclear, as mutations accumulate with age and are considered a molecular clock of both healthy and premalignant hematopoiesis [5]. CH origins and subsequent dynamics are genotype specific, as some clones could spontaneously disappear [6]. For instance, DNMT3A-mutant clones quickly arise during youth, while slowdown in adulthood and elderly, often replaced by TET2- or splicing factor–mutated CH. Clone fitness is also context dependent. Chemotherapy and radiation are major selection pressures, strongly influencing genotype-dependent clonal expansion, dominance, or attrition [7], as clonal growth is faster for TP53, PPM1D, and CHEK2 in individuals undergoing chemo/radiotherapy [8]. Moreover, a VAF threshold of ≥2% has been proposed as cut-off for clonal evolution: when CH clones reach that value, they are more commonly linked to malignant and nonmalignant outcomes [9].

CH is an evolving concept from a strictly neoplastic to a more dynamic and evolutionary framework, where it might reflect the stem cell pool diversity in a certain moment in the bone marrow (BM), like a snapshot of panta rei hematopoiesis. Conventionally, clonal evolution is defined as the selection of malignant clones under continuous external pressures, eventually leading to cancer. However, with routinely use of next-generation sequencing (NGS), CH is frequently found with ageing and some chronic conditions, without accompanying with cancer disorders [10], as clonal dynamics can be influenced by DNA-damaging stimuli and stress hematopoiesis [11, 12]. Clones carrying pathogenic variants, that could randomly occur in the BM, might remain quiescent or minimally proliferate for years, and only expand under certain stressors, such as infections or post-HSC infusion [13]. In ovarian cancers, after HSP90 or PARP inhibitor treatments, TP53- and PPM1D-mutated clones expand faster than DNMT3A- or TET2-mutated clones. Moreover, clones with co-occurring somatic mutations in DNA damage response (DDR) genes and germline mutations in homologous recombination genes have reduced proliferation capacity [11]. During these stressful events, clones temporarily appear and return under the detection level once these conditions resolve, as observed during BM reconstitution after HSC transplantation (HCT) or acute myeloid leukemia (AML) relapse [11, 14, 15]. During reconstitution, recipients gain an average of ~23 mutations, equivalent to ~1.5 years of ageing, with driver mutations in DNMT3A and TET2 [11]. Similarly, DNMT3A, TP53, and TET2 are more frequently found at AML relapse compared to diagnosis, as well as RUNX1, FLT3-tyrosine kinase domain, PTPN11, IKZF1, and KIT [15], reflecting the preferential growth of fitter clones under stress [11]. However, fitness does not always correlate with effective hematopoiesis and older donor-derived stem cells often show lineage bias and poor responsiveness to stress, leading to ineffective hematopoiesis [16].

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Fig. 1: The “emergency clonal escape” theory.
Fig. 2: The speed of leukemia.

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Acknowledgements

This research was supported by the Intramural Program of the Department of Medicine, Surgery and Dentistry, University of Salerno, Italy.

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  1. Department of Medicine, Surgery, and Dentistry, University of Salerno, 84081, Baronissi, Italy

    Valentina Giudice & Carmine Selleri

  2. Hematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131, Salerno, Italy

    Valentina Giudice & Carmine Selleri

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Conceptualization, VG, and CS; writing—original draft preparation, VG; writing—review and editing, CS. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Valentina Giudice or Carmine Selleri.

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Giudice, V., Selleri, C. How fast does leukemia progress?. Leukemia 39, 805–809 (2025). https://doi.org/10.1038/s41375-025-02536-3

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