Project A1: The contribution of mechanisms of aging of HSCs to leukemia initiation and progression

Myelodysplastic syndrome (MDS) and AML are diseases of the elderly. The contribution of aging to these diseases has been previously primarily regarded as time for selection of abnormal clones. Aging of HSCs is caused by defined molecular mechanisms, and upon aging the function of HSCs and of the HSC niche changes, which might impact directly on the process of selection of HSCs within the bone marrow. It is also a possibility that the transition of MDS to AML in the elderly is in part a consequence of molecular mechanisms of aging of HSCs. MDS or AML thus might be, based on our novel concept, a disease in which expansion/selection of the fittest (but differentiation impaired) HSC clone (like a p53-/- HSC) is at least in part driven by molecular changes that cause aging of HSCs. We will test whether molecular mechanisms that drive aging of HSCs and/or aging of HSC niches which confer aging on HSCs might mechanistically and causatively contribute to the initiation and progression of MDS or AML, and whether pharmacological approaches that attenuate aging of HSCs might be novel approaches to attenuate initiation and/or progression of MDS.

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