title: Molecular basis of aggressive disease in chronic lymphocytic leukemia patients with 11q deletion and trisomy 12 chromosomal abnormalities.
abstract: In B-cell chronic lymphocytic leukemia (CLL), Rai stage, immunoglobulin gene mutational status, chromosomal abnormalities, CD38 and ZAP-70 expression were used as prognostic markers. In this study, to understand the molecular basis of chromosomal abnormalities leading to tumor progression, 90 CLL patients were grouped into poor prognosis (with 11q deletion and trisomy 12) and good prognosis (with normal karyotype and 13q deletion) and their clinical outcome was assessed. Gene expression profiles of 35 CLL samples with poor outcome (11q deletion, n=9; trisomy 12, n=5) and good outcome (13q deletion, n=13; normal karyotype, n=8) were analyzed using oligonucleotide microarray. Significance analysis of microarray (SAM) identified 27 differentially expressed genes between these two subgroups with significant overexpression of ATF5 and underexpression of CDC16, PCDH8, SLAM, MNDA and ATF2 in CLL patients with poor outcome. ATF5 gene expression in CLL was further studied because of its role in the regulation of cell cycle progression/differentiation and apoptosis. The overexpression of ATF5 was confirmed by real-time PCR using 39 CLL samples from the poor and good outcome groups. ATF5 was significantly (p<0.001) overexpressed in the poor outcome group. Furthermore, ATF5 expression was significantly higher in the 11q deletion as well as trisomy 12 group alone compared to the 13q deletion and normal karyotype groups. ATF5 overexpression was also associated with significantly (p=0.04) shorter time to treatment. Similarly, expression of five underexpressed genes also correlated with longer time to treatment. Thus, this report demonstrates that ATF5 may be one of the key genes involved in increased proliferation and survival in 11q deletion or trisomy 12, whereas CD16, CD86, SLAM, MNDA and ATF2 may be involved in the decreased proliferation of CLL cells with 13q deletion or normal karyotype.
authors.affiliation: Department of Genetics, University of Nebraska Medical Center, Omaha, NE 68198-6395, USA.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mittal
authors.forename: Ganapati V
authors.initials: GV
authors.lastname: Hegde
authors.forename: Patricia
authors.initials: P
authors.lastname: Aoun
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bociek
authors.forename: Bhavana J
authors.initials: BJ
authors.lastname: Dave
authors.forename: Avadhut D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Warren G
authors.initials: WG
authors.lastname: Sanger
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
mesh_terms: D051696:Activating Transcription Factors / Q000378:metabolism; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D016000:Cluster Analysis; D020732:Cytogenetic Analysis; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013997:Time Factors; D016896:Treatment Outcome; D014314:Trisomy / Q000235:genetics*