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Updated: Mar 29, 2026
Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome
Published on: October 3, 2018
SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment
Syed A Mian1, Kevin Rouault-Pierre2, Alexander E Smith1,3
1Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.
Abstract:
Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+) HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target.
Insights
SF3B1 mutations in myelodysplastic syndrome (MDS) originate in hematopoietic stem cells (HSCs). These mutations initiate disease, propagate to myeloid cells, and can lead to acute myeloid leukemia (AML) transformation.
Area of Science:
- Hematology
- Cancer Biology
- Stem Cell Biology
Background:
- Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders.
- The cellular origin of MDS, particularly in non-5q-MDS subtypes, remains incompletely understood.
- While MDS stem cells are known in 5q-MDS, their role in other MDS subgroups requires clarification.
Purpose of the Study:
- To investigate whether hematopoietic stem cells (HSCs) are the initiating cells in MDS with ring sideroblasts (MDS-RS).
- To determine if SF3B1 mutations, common in MDS-RS, arise from HSCs and drive disease pathogenesis.
- To explore the clonal evolution and potential for malignant transformation of SF3B1-mutant HSCs.
Main Methods:
- Analysis of SF3B1 mutations in patient cohorts.
- Isolation and characterization of CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+) HSCs.
- Xenotransplantation of SF3B1-mutant HSCs into immunocompromised mice.
- Longitudinal monitoring of engraftment, lineage commitment, and clonal evolution in vivo.
- Sequential analysis of patient samples to correlate with preclinical findings.
Main Results:
- SF3B1 mutations in MDS-RS patients were found to originate from specific HSC populations.
- Xenotransplantation of SF3B1-mutant HSCs resulted in sustained myeloid engraftment in mice.
- Genetically diverse subclones of SF3B1-mutant HSCs emerged in mice, demonstrating multi-clonal evolution.
- Observed clonal evolution in mice mirrored clinical progression in patients, including transformation to acute myeloid leukemia (AML).
Conclusions:
- SF3B1 mutations can originate and propagate from HSCs in MDS-RS.
- SF3B1-mutant HSCs are capable of initiating MDS pathogenesis and undergoing clonal evolution.
- The findings identify SF3B1-mutant HSCs as a key driver of MDS and a potential therapeutic target.
