Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML

Blood Cancer J. 2014 May 2;4(5):e208. doi: 10.1038/bcj.2014.27.

Abstract

Patients with high FLT3 internal tandem duplication allelic ratios (FLT3/ITD-ARs) have a poor prognosis. Single-nucleotide polymorphism/comparative genomic hybridization, single-cell PCR and colony-forming assays were used to evaluate genotypic evolution of high FLT3/ITD-ARs in 85 acute myeloid leukemia (AML) patients. Microarrays were used to examine molecular pathways disrupted in leukemic blasts with high FLT3/ITD-ARs. Copy-neutral loss of heterozygosity (CN-LOH) was identified at the FLT3 locus in diagnostic samples with high FLT3/ITD-ARs (N=11), but not in samples with low FLT3/ITD-ARs (N=24), FLT3-activating loop mutations (N=11) or wild-type FLT3 (N=39). Single-cell assays showed that homozygous FLT3/ITD genotype was present in subsets of leukemic blasts at diagnosis but became the dominant clone at relapse. Less differentiated CD34(+)/CD33(-) progenitor colonies were heterozygous for FLT3/ITD, whereas more differentiated CD34(+)/CD33(+) progenitor colonies were homozygous for FLT3/ITD. Expression profiling revealed that samples harboring high FLT3/ITD-ARs aberrantly expressed genes within the recombination/DNA repair pathway. Thus, the development of CN-LOH at the FLT3 locus, which results in high FLT3/ITD-ARs, likely represents a late genomic event that occurs after the acquisition of the FLT3/ITD. Although the etiology underlying the development of CN-LOH remains to be clarified, the disruption in recombination/DNA repair pathway, which is present before the development of LOH, may have a role.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Child
  • Genotype
  • Humans
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Loss of Heterozygosity*
  • Neoplasm Recurrence, Local / enzymology
  • Neoplasm Recurrence, Local / genetics
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Tandem Repeat Sequences
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3