Myelodysplastic syndrome (MDS) is a heterogeneous group of related clonal diseases with increasing incidence and prevalence, characterized by variable cytopenias due to ineffective hematopoiesis. A subset of MDS patients may also progress to secondary acute myeloid leukemia. There is considerable hope, however, that through a better understanding of MDS pathogenesis, novel therapeutics can alleviate or even correct these deficiencies. Beyond hypomethylating agents, which have variable response rates and duration of effect, no such therapy has been approved. We have previously shown that MDS is a disease of the hematopoietic stem cell (HSC).
Aim 1 of this proposal describes a method to use fluorescence-activated cell sorting to deplete CD69hi and CD99hi MDS HSCs from the residual CD69lo CD99- normal HSCs to facilitate autologous stem cell transplantation as therapy. Effectiveness of separation will be functionally evaluated via transplantation into immunodeficient mouse strains, an assay we have previously shown to distinguish between normal cells and MDS cells. Combined with a promising novel non-toxic conditioning regime being developed clinically at Stanford (separately from this proposal), autologous stem cell transplantation may serve as a novel potential treatment for MDS.
Aim 2 is to detect mutations in MDS at the single cell level. Through whole exome sequencing of MDS myeloblasts and progenitors, in conjunction with TaqMan SNP genotyping of individual HSC clones, we will address three fundamental questions to better characterize MDS for potential future therapeutic interventions: (1) in what order do these mutations occur? (2) do all the MDS mutations occur in the HSC pool? and (3) which mutations correlate with the conversion of a normal HSC to an MDS HSC and then to an LSC? The ordered series of mutations will provide insight into the mechanisms of disease, especially in understanding whether a stereotypical sequences of events occurs in pathogenesis and progression. Furthermore, we expect that identifying the specific mutations that occur at the transition between normal and MDS hematopoiesis will reveal critical targets for potential therapeutic interventions. Both of the aims capitalize on our knowledge of hematopoietic stem cells. These studies have the potential to offer a new application of bone marrow transplantation in the treatment of MDS and to characterize the disease mechanism to facilitate discovery of future therapies.

Public Health Relevance

Myelodysplastic syndrome is a disease of aging in the blood stem cell. This proposal aims to test a potential treatment strategy and to identify the key mutations in disease, which will provide insight into the mechanism of disease and potential therapeutic targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Welniak, Lisbeth A
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Stanford University
Anatomy/Cell Biology
Schools of Medicine
United States
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Chen, James Y; Miyanishi, Masanori; Wang, Sean K et al. (2016) Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature 530:223-7
Mori, Yasuo; Chen, James Y; Pluvinage, John V et al. (2015) Prospective isolation of human erythroid lineage-committed progenitors. Proc Natl Acad Sci U S A 112:9638-43