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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1684-1689. Prepublished online as a Blood First Edition Paper on May 11, 2006; DOI 10.1182/blood-2005-11-011486. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2005-11-011486v1 108/5/1684    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Stephens, K. Articles by Shannon, K. M Search for Related Content PubMed PubMed Citation Articles by Stephens, K. Articles by Shannon, K. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 22, 2005 Accepted April 24, 2006 Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies Karen Stephens*, Molly Weaver, Kathleen A Leppig, Kyoko Maruyama, Peter D Emanuel, Michelle M Le Beau, and Kevin M Shannon Departments of Medicine, Laboratory Medicine, University of Washington, Seattle, WA, USA Departments of Medicine, University of Washington, Seattle, WA, USA Department of Pediatrics, University of Washington, Seattle, WA, USA Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, AL, USA Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA Department of Pediatrics and Comprehensive Cancer Center, University of California, San Francisco,CA * Corresponding author; email: millie{at}u.washington.edu. To identify the mechanism of loss of heterozygosity (LOH) and potential modifier gene(s), we investigated the molecular basis of somatic NF1 inactivation in myeloid malignancies from ten children with neurofibromatosis type 1. Loci across a minimal 50 Mb region of primarily the long arm of chromosome 17 showed LOH in 8 cases, whereas a <9 Mb region of loci flanking NF1 had LOH in the remaining 2 cases. Two complementary techniques, quantitative PCR and fluorescence in situ hybridization (FISH), were employed to determine if the copy number at loci that showed LOH was one or two (i.e., deleted or isodisomic). The 2 cases with LOH limited to <9 Mb were intrachromosomal deletions. Among the 8 leukemias with 50 Mb LOH segments, four had partial uniparental isodisomy and four had interstitial uniparental isodisomy. These isodisomic cases showed clustering of the centromeric and telomeric LOH breakpoints. This suggests that the cases with interstitial uniparental isodisomy arose in a leukemia- initiating cell by double homologous recombination events at intervals of preferred mitotic recombination. Homozygous inactivation of NF1 favored outgrowth of the leukemia-initiating cell. Our studies demonstrate that LOH analyses of loci distributed along the chromosomal length along with copy-number analysis can reveal novel mechanisms of LOH that may potentially identify regions harboring " cryptic" tumor suppressor or modifier genes whose inactivation contribute to tumorigenesis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. W. Vardiman, J. Thiele, D. A. Arber, R. D. Brunning, M. J. Borowitz, A. Porwit, N. L. Harris, M. M. Le Beau, E. Hellstrom-Lindberg, A. Tefferi, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood, July 30, 2009; 114(5): 937 - 951. [Abstract] [Full Text] [PDF] B. Lange A FISH 'n chips appetizer Blood, January 15, 2008; 111(2): 480 - 481. [Full Text] [PDF] C. Flotho, C. P. Kratz, and C. M. Niemeyer How a rare pediatric neoplasia can give important insights into biological concepts: a perspective on juvenile myelomonocytic leukemia Haematologica, November 1, 2007; 92(11): 1441 - 1446. [Full Text] [PDF] A. Mohamedali, J. Gaken, N. A. Twine, W. Ingram, N. Westwood, N. C. Lea, J. Hayden, N. Donaldson, C. Aul, N. Gattermann, et al. Prevalence and prognostic significance of allelic imbalance by single-nucleotide polymorphism analysis in low-risk myelodysplastic syndromes Blood, November 1, 2007; 110(9): 3365 - 3373. [Abstract] [Full Text] [PDF] J. Suela, C. Largo, B. Ferreira, S. Alvarez, M. Robledo, A. Gonzalez-Neira, M. J. Calasanz, and J. C. Cigudosa Neurofibromatosis 1, and Not TP53, Seems to Be the Main Target of Chromosome 17 Deletions in De Novo Acute Myeloid Leukemia J. Clin. Oncol., March 20, 2007; 25(9): 1151 - 1152. [Full Text] [PDF] F. G. Rucker, L. Bullinger, K. Dohner, and H. Dohner In Reply J. Clin. Oncol., March 20, 2007; 25(9): 1152 - 1153. [Full Text] [PDF]

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