Whole-genome analysis reveals unexpected dynamics of mutant subclone development in a patient with JAK2-V617F-positive chronic myeloid leukemia

Exp Hematol. 2017 Sep;53:48-58. doi: 10.1016/j.exphem.2017.05.007. Epub 2017 Jun 8.


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+/JAK2V617F-mutant cells and, over a 9-year period, progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS revealed that 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 six additional coding somatic mutations, despite retention by the hematopoietic progeny of the parental AP cell levels of BCR-ABL1 expression and sensitivity to imatinib and pimozide. Limited analysis of BP cells revealed independent subclonal progression to homozygosity of the MAD1L1 and RREB1 variants. MAD1L1 and SEC23B mutations were also identified in 2 of 101 cases of myeloproliferative neoplasms, but not in 42 healthy subjects. These findings challenge historic concepts of clonal evolution in CML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Genome-Wide Association Study
  • Humans
  • Induced Pluripotent Stem Cells / physiology
  • Janus Kinase 2 / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Nuclear Proteins / genetics
  • Transcription Factors / genetics


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MAD1L1 protein, human
  • Nuclear Proteins
  • RREB1 protein, human
  • Transcription Factors
  • JAK2 protein, human
  • Janus Kinase 2

Grant support