Quantitative PCR identifies a minimal deleted region of 120 kb extending from the Philadelphia chromosome ABL translocation breakpoint in chronic myeloid leukemia with poor outcome.
Fluorescence in situ hybridization (FISH) analysis has shown previously that 10-15% of chronic myeloid leukemias (CML) have hemizygous deletions of variable sizes affecting regions that flank the ABL and BCR translocation breakpoints on the derivative chromosome 9, and these patients have a poor outcome. FISH studies using large commercial genomic probes have previously suggested that haploinsufficiency of sequences flanking either ABL or BCR modify the disease process of CML and lead to an unfavorable prognosis. In this present study, real-time quantitative PCR (Q-PCR) analysis was used to identify and map much smaller hemizygous microdeletions in a subset of CML patients that were not deleted using large genomic FISH probes. Microdeletions were identified by Q-PCR in 25 of 71 patients selected based on less favorable outcome (chronic phase duration of less than 96 months and a survival time of less than 84 months). In contrast, no microdeletion was detected in any of 18 CML samples selected from a group with a more favorable outcome. Detailed mapping of the 25 Q-PCR microdeletions showed that the minimal deleted region extended approximately 120 kb from the 5' end of the ABL gene in the centromeric direction on the derivative chromosome 9, and the region 3' to BCR on chromosome 22 was excluded. Of the four ESTs and/or genes that map to the 120 kb region, the putative tumor suppressor PRDM12 is the strongest candidate gene. The potential role for each sequence in modifying the clinical behavior of CML is presented.
Kolomietz
E
E
Ontario Cancer Institute, Toronto, Ontario, Canada.
Marrano
P
P
Yee
K
K
Thai
B
B
Braude
I
I
Kolomietz
A
A
Chun
K
K
Minkin
S
S
Kamel-Reid
S
S
Minden
M
M
Squire
J A
JA
D019457:Chromosome Breakage; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D015331:Cohort Studies; D016147:Genes, Tumor Suppressor; D016313:Genes, abl / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D010677:Philadelphia Chromosome; D016133:Polymerase Chain Reaction / Q000379:methods*; D011379:Prognosis; D015996:Survival Rate