PMID- 16690971
OWN - NLM
STAT- MEDLINE
DCOM- 20061005
LR  - 20231105
IS  - 0006-4971 (Print)
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 108
IP  - 5
DP  - 2006 Sep 1
TI  - Interstitial uniparental isodisomy at clustered breakpoint intervals is a 
      frequent mechanism of NF1 inactivation in myeloid malignancies.
PG  - 1684-9
AB  - 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 10 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 less than 9-Mb region of loci flanking NF1 had LOH in the 
      remaining 2 cases. Two complementary techniques, quantitative polymerase chain 
      reaction (PCR) and fluorescence in situ hybridization (FISH), were used to 
      determine whether the copy number at loci that showed LOH was 1 or 2 (ie, deleted 
      or isodisomic). The 2 cases with LOH limited to less than 9 Mb were 
      intrachromosomal deletions. Among the 8 leukemias with 50-Mb LOH segments, 4 had 
      partial uniparental isodisomy and 4 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 contributes to tumorigenesis.
FAU - Stephens, Karen
AU  - Stephens K
AD  - Department of Medicine, University of Washington, Medical Genetics 357720, 
      Seattle, WA 98195, USA. millie@u.washington.edu
FAU - Weaver, Molly
AU  - Weaver M
FAU - Leppig, Kathleen A
AU  - Leppig KA
FAU - Maruyama, Kyoko
AU  - Maruyama K
FAU - Emanuel, Peter D
AU  - Emanuel PD
FAU - Le Beau, Michelle M
AU  - Le Beau MM
FAU - Shannon, Kevin M
AU  - Shannon KM
LA  - eng
GR  - K24 CA80916/CA/NCI NIH HHS/United States
GR  - P01 CA40046/CA/NCI NIH HHS/United States
GR  - R01 CA72614/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20060511
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Neurofibromin 1)
SB  - IM
MH  - Age of Onset
MH  - Child, Preschool
MH  - Chromosome Mapping
MH  - *Chromosomes, Human, Pair 17
MH  - Female
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Infant
MH  - Leukemia, Myeloid/*genetics
MH  - Loss of Heterozygosity
MH  - Male
MH  - Neurofibromatosis 1/*genetics
MH  - Neurofibromin 1/*genetics
MH  - Recombination, Genetic
MH  - Uniparental Disomy/*genetics
PMC - PMC1895516
EDAT- 2006/05/13 09:00
MHDA- 2006/10/06 09:00
PMCR- 2007/09/01
CRDT- 2006/05/13 09:00
PHST- 2006/05/13 09:00 [pubmed]
PHST- 2006/10/06 09:00 [medline]
PHST- 2006/05/13 09:00 [entrez]
PHST- 2007/09/01 00:00 [pmc-release]
AID - S0006-4971(20)52641-4 [pii]
AID - 1684 [pii]
AID - 10.1182/blood-2005-11-011486 [doi]
PST - ppublish
SO  - Blood. 2006 Sep 1;108(5):1684-9. doi: 10.1182/blood-2005-11-011486. Epub 2006 May 
      11.