MDS is a heterogeneous group of myeloid disorders marked by accumulation of oncogenic mutations in hematopoietic stem cells (HSCs). The clonal history and functional significance of premalignant mutations remains poorly understood. In this paper, we used iPSC reprogramming to capture genetically distinct subclones in MDS and myeloid cancers, and trace the clonal history of somatic mutations. The earliest premalignant cells could be identified by reprogramming even when undetectable in patients. By differentiating subclonal MDS iPSCs to hematopoietic stem and progenitor cells we recapitulate disease progression and identify cooperating mutations in individual patients. We are grateful to all of our collaborators and support from NHLBI, NIH Common Fund, EvansMDS Foundation, UW/FHCRC Cancer Consortium, and Tietze family.