Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML.
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.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Stirewalt
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Pogosova-Agadjanyan
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Pathology, Seattle Children's Hospital, Seattle, WA, USA [3] Department of Laboratory Medicine, University of Washington Medical Center, Seattle, WA, USA.
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Tsuchiya
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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Joaquin
1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Pediatrics, University of Washington Medical Center, Seattle, WA, USA [3] Children's Oncology Group, Arcadia, CA, USA [4] Department of Hematology-Oncology, Seattle Children's Hospital, Seattle, WA, USA.
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Meshinchi
D000483:Alleles; D002648:Child; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3