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 leuk...

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Main Authors:	Stirewalt, D L, Pogosova-Agadjanyan, E L, Tsuchiya, K, Joaquin, J, Meshinchi, S
Format:	Online
Language:	English
Published:	Nature Publishing Group 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042297/

id	pubmed-4042297
recordtype	oai_dc
spelling	pubmed-40422972014-06-12 Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML Stirewalt, D L Pogosova-Agadjanyan, E L Tsuchiya, K Joaquin, J Meshinchi, S Original Article 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. Nature Publishing Group 2014-05 2014-05-02 /pmc/articles/PMC4042297/ /pubmed/24786392 http://dx.doi.org/10.1038/bcj.2014.27 Text en Copyright © 2014 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-sa/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Stirewalt, D L Pogosova-Agadjanyan, E L Tsuchiya, K Joaquin, J Meshinchi, S
spellingShingle	Stirewalt, D L Pogosova-Agadjanyan, E L Tsuchiya, K Joaquin, J Meshinchi, S Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML
author_facet	Stirewalt, D L Pogosova-Agadjanyan, E L Tsuchiya, K Joaquin, J Meshinchi, S
author_sort	Stirewalt, D L
title	Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML
title_short	Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML
title_full	Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML
title_fullStr	Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML
title_full_unstemmed	Copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of FLT3/ITD AML
title_sort	copy-neutral loss of heterozygosity is prevalent and a late event in the pathogenesis of flt3/itd aml
description	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.
publisher	Nature Publishing Group
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042297/
_version_	1612095651984703488

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

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