Genetic analysis of dasatinib-treated chronic myeloid leukemia rapidly developing into acute myeloid leukemia with monosomy 7 in Philadelphia-negative cells

Cancer Genet Cytogenet. 2010 Jun;199(2):89-95. doi: 10.1016/j.cancergencyto.2010.02.005.

Abstract

Despite the recent success of tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), approximately 2-17% of patients develop clonal cytogenetic changes in the Philadelphia-negative (Ph(-)) cell population. A fraction of these patients, in particular those displaying trisomy 8 or monosomy 7, are at risk of developing a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Consequently, there is a need to characterize the clinical features of such cases and to increase our understanding of the pathogenetic mechanisms underlying the emergence of clonal cytogenetic changes in Ph(-) cells. To date, most cases reported have received treatment with imatinib. Here we describe the case of a patient with CML who developed monosomy 7 in Ph(-) cells during dasatinib therapy. At 20 months after dasatinib initiation, the patient developed MDS, which rapidly progressed into AML. Genome-wide 500K SNP array analysis of the monosomy 7 clone revealed no acquired submicroscopic copy number changes. Given the strong association between monosomy 7 and mutation of genes involved in the RAS pathway in juvenile myelomonocytic leukemia, we also screened for pathogenetic variants in KRAS, NRAS, and PTPN11, but did not detect any changes.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosomes, Human, Pair 7 / genetics*
  • Dasatinib
  • Female
  • Genes, ras / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Karyotyping
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Leukemia, Myeloid, Acute / chemically induced
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / chemically induced
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / genetics*
  • Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / pathology
  • Middle Aged
  • Monosomy*
  • Mutation / genetics
  • Myelodysplastic Syndromes / chemically induced
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / pathology
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Pyrimidines / therapeutic use*
  • Thiazoles / therapeutic use*
  • ras Proteins / genetics

Substances

  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Pyrimidines
  • Thiazoles
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • Dasatinib