The myelodysplastic syndromes (MDS) are cancers of the bone marrow (BM) that cause low blood counts and an increased risk for leukemia. MDS starts in and is sustained by mutated blood-forming stem cells called MDS stem cells. The best drugs for MDS can improve blood counts, but they never get rid of MDS stem cells. As a result, MDS can only be cured by replacing MDS stem cells with healthy stem cells in a BM transplant. However, 40% of patients relapse after transplant, and preventing such relapses is critical to improving cure rates. It is challenging to study blood-forming stem cells because they are very rare. We developed a DNA sequencing technique capable of detecting MDS stem cells amo...

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The myelodysplastic syndromes (MDS) are cancers of the bone marrow (BM) that cause low blood counts and an increased risk for leukemia. MDS starts in and is sustained by mutated blood-forming stem cells called MDS stem cells. The best drugs for MDS can improve blood counts, but they never get rid of MDS stem cells. As a result, MDS can only be cured by replacing MDS stem cells with healthy stem cells in a BM transplant. However, 40% of patients relapse after transplant, and preventing such relapses is critical to improving cure rates. It is challenging to study blood-forming stem cells because they are very rare. We developed a DNA sequencing technique capable of detecting MDS stem cells among small numbers of blood-forming stem cells. Using this technique, we found that detection of MDS stem cells at early time points after transplant is associated with a 100% relapse rate, with detection often preceding clinical relapse by many months. We will use our DNA sequencing technique to test for MDS stem cells persisting after transplant in ~300 patients over a three-year period. We will first determine if this test can identify nearly all patients destined to relapse well before it happens. This would enable the design of clinical trials to test new therapies to prevent relapse. Second, we have identified proteins present on MDS stem cells but not normal blood stem cells. We will test if detection of MDS stem cells using these proteins can be used to monitor patients for relapse from a simple blood test. Finally, to understand how MDS stem cells persist after transplant, we will test if they persist in a random manner or by evading the immune system. We will then use a new single cell sequencing technique to study their molecular features in the post-transplant setting to identify therapeutic vulnerabilities. Together, this work promises to identify new treatment strategies to extend the curative potential of transplant to more MDS patients.

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