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- Early clone formation. Mutations that trigger myelodysplastic syndromes (MDS) often arise prenatally or during childhood; clone specificity and mutation determine the risk for progression.
- Microenvironment as a driver. Only age-related changes and chronic inflammation of the niche enable the selection and expansion of the clone.
- Therapeutic implication. Successful disease control requires a dual approach targeting both clonal mutations and niche interactions.
The two perspectives — “It’s all about the clone!” and “The niche is the key!” — were presented by Klaus Metzeler, University Hospital Leipzig, Leipzig, Germany, and Tata Nageswara Rao, Cantonal Hospital St. Gallen, St. Gallen, Switzerland, during a debate at the Annual Meeting of the German-Speaking Societies for Hematology and Medical Oncology.
Clonus: Mutations Early in Life
Both speakers examined the precursors of MDS and acute myeloid leukemia — clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance.
Metzeler emphasized that MDS-triggering mutations arise very early in life, many of them during childhood and adolescence, and some even before birth. The age of a clone can be accurately determined through serial sequencing and mathematical models. Lifestyle, comorbidities, and environmental factors acquired later in life therefore cannot yet play a role.
Rapid expansion occurs early in life, during the development of the hematopoietic system. However, as life progresses, clones with MDS driver mutations expand only slowly.
- MDS clones often arise prenatally/childhood; progression depends on clone + mutation.
- High-risk genes: SRSF2, IDH, TP53, U2AF1, RUNX1; TET2/DNMT3A lower risk.
- Clone size + mutation count refine progression risk; used in molecular prognostic scores.
- Aging/inflammation niche enables clonal expansion; CHIP→neoplasm ~0.5%-1%/year.
- Dual targeting clone + niche may improve control; anti-inflammatory monotherapy has limited hematologic benefit.
Clone: MDS Driver Mutations Influence Inflammation
A study of patients with COVID found that inflammatory profiles varied by MDS driver mutation, with specific mutations, including TET2 and DNMT3A, associated with distinct immune cell compositions.
Clone: Driver of Progression Risk
Not all MDS mutations are equally harmful, according to Metzeler. TET2 and DNMT3A carry only a low risk for progression, whereas SRSF2, IDH, TP53, U2AF1, and RUNX1 are high-risk genes. The number of mutations and clone size also influence the risk for progression.
Therefore, the presence of a high-risk mutation is usually the first decisive criterion in clinical decision trees and integrated risk scores (eg, the Molecular International Prognostic Scoring System).
Clone: Targeted Therapies Are Successful
Metzeler cited, as a key argument, that targeted therapies against specific mutations have been successfully tested in clinical trials. Examples of good therapeutic responses include enasidenib ± azacitidine for IDH2 mutations and ivosidenib for IDH1 mutations.
In contrast, anti-inflammatory therapies have so far been largely unsuccessful. Although canakinumab and emavusertib demonstrated effects on inflammation, they showed virtually no hematologic response.
Niche: Clones Are Common, Diseases Are Rare
At the start of his rebuttal, Rao pointed out the statistics. Between 10% and 20% of people over the age of 70 carry a detectable clone. However, progression from CHIP to a neoplasm occurs in only 0.5%-1% of cases per year. Thus, it is not the mutation alone that determines the course of the disease; rather, other factors play a decisive role in the development of MDS.
Furthermore, there is a long latency period between the emergence of the mutated clone — before birth or during childhood — and diagnosis. This raises the question of what influences the expansion.
Niche: Age and Inflammation Are the Most Important Risk Factors
Aging is the most important single risk factor for MDS. Changes occur in the clones’ environment, such as sympathetic denervation, reduced C-X-C motif chemokine ligand 12 and stem cell factor levels, chronically active proinflammatory signaling pathways, and accumulated DNA damage.
Inflammation leads to the selection of mutated hematopoietic stem cells, which exploit the altered niche to their advantage.The mutated clone survives in the niche, which is unfavorable for normal stem cells. In a mouse model, interleukin 1 leads to TET2 expansion.
Niche: Also a Target for Therapy
The niche allows for clonal expansion, determines the fibrotic and dysplastic phenotype, and offers genetically stable, nonresistant therapeutic targets, according to Rao. A number of different drugs are in various phases of clinical trials. One example is the S100A8/A9 inflammatory axis, which can be blocked by tasquinimod. In animal models, this leads to a reduction in splenic disease and bone marrow fibrosis.
Experimental modifications of the niche result in an altered clinical picture. Biological signals and effects are also evident in humans. Activation of the immune system can also lead to the control of pathogenic clones. Effective disease control is only possible by targeting the clone and its pathogenic interactions, Rao concluded.
This story was translated from Coliquio, part of the Medscape Professional Network.
