Abstract We report here the first use of whole genome sequencing (WGS) to examine the initial clonal dynamics in an unusual patient with chronic myeloid leukemia (CML) who presented in chronic phase (CP) with doubly marked BCR-ABL1+ / JAK2 V617F -mutant cells and over a 9 year period progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS showed the diagnostic cells also contained mutations in ASXL1, SEC23B , MAD1L1 and RREB1, as well as 12,000 additional uncommon DNA variants. WGS of endothelial cells generated from circulating precursors revealed many of these were shared with the CML clone. Surprisingly, WGS of induced pluripotent stem cells (iPSCs) derived from the AP cells revealed only 6 additional coding somatic mutations despite retention by their hematopoietic progeny of the parental AP cell levels of BCR-ABL1 expression and sensitivity to imatinib and pimozide. Limited analysis of BP cells showed independent subclonal progression to homozygosity of the MAD1L1 and RREB1 variants. MAD1L1 and SEC23B mutations were also identified in 2/101 cases of myeloproliferative neoplasms but not in 42 healthy subjects. These findings challenge historic concepts of clonal evolution in CML.