Clonal evolution revealed by whole genome sequencing in a case of primary myelofibrosis transformed to secondary acute myeloid leukemia

Leukemia. 2015 Apr;29(4):869-76. doi: 10.1038/leu.2014.289. Epub 2014 Sep 25.


Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / pathology
  • Clonal Evolution / genetics*
  • Clone Cells
  • Core Binding Factor Alpha 2 Subunit / genetics
  • Disease Progression
  • Female
  • Gene Expression
  • Genome, Human*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Janus Kinase 2 / genetics
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Middle Aged
  • Mutation Rate
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Primary Myelofibrosis / genetics*
  • Primary Myelofibrosis / pathology
  • Proto-Oncogene Proteins c-myb / genetics
  • Repressor Proteins / genetics
  • Ribonucleoproteins / genetics
  • Splicing Factor U2AF


  • ASXL1 protein, human
  • Core Binding Factor Alpha 2 Subunit
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myb
  • RUNX1 protein, human
  • Repressor Proteins
  • Ribonucleoproteins
  • Splicing Factor U2AF
  • U2AF1 protein, human
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • JAK2 protein, human
  • Janus Kinase 2