title: The Genomic Landscape of PAX5, IKZF1, and CDKN2A/B Alterations in B-Cell Precursor Acute Lymphoblastic Leukemia.
abstract: We present a comprehensive comparison of PAX5,IKZF1, and CDKN2A/B abnormalities in 21 B-cell precursor acute lymphoblastic leukemia (B-ALL) patients studied by aCGH and gene-specific FISH assays. In our cohort of B-ALL patients, alterations of IKZF1, PAX5, and CDKN2A/B were detected by aCGH analysis in 43, 52, and 57% of samples, respectively. Deletions of IKZF1 were present in 9 samples, including 5 cases positive for both PAX5 and IKZF1 deletions, implying digenic impairment. Furthermore, all cases with IKZF1 deletions also had additional genomic alterations, including BCR-ABL1 gene fusions, PAX5 deletions, CDKN2A/B deletions, and FLT3 amplification. Deletions of CDKN2A/B represented the most frequent abnormalities in our group of patients. Our study demonstrates the high incidence of PAX5, IKZF1, and CDKN2A/B alterations in B-ALL detected by aCGH analysis. Due to the small size and variability in the deletion breakpoints, FISH studies showed false-negative results in 10, 40, and 28% of the samples tested for the IKZF1,PAX5, and CDKN2A/B gene deletions, respectively. The PAX5 and IKZF1 abnormalities are highly specific to B-ALL and can be used as diagnostic markers. Moreover, IKZF1 alterations frequently coexist with a BCR-ABL gene fusion. Our study revealed multiple additional B-ALL-specific genomic alterations and showed that aCGH is a more sensitive method than FISH, allowing whole genome profiling and identification of aberrations of diagnostic and prognostic significance in patients with B-ALL.
authors.affiliation: Center for Clinical Genetics and Genomics, Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
authors.forename: Zhishuo
authors.initials: Z
authors.lastname: Ou
authors.forename: Maureen
authors.initials: M
authors.lastname: Sherer
authors.forename: Jane
authors.initials: J
authors.lastname: Casey
authors.forename: Heather A
authors.initials: HA
authors.lastname: Bakos
authors.forename: Kathleen
authors.initials: K
authors.lastname: Vitullo
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.forename: Erika
authors.initials: E
authors.lastname: Friehling
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Gollin
authors.forename: Urvashi
authors.initials: U
authors.lastname: Surti
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Yatsenko
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D055028:Comparative Genomic Hybridization; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D017353:Gene Deletion; D019942:Genes, p16; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015448:Leukemia, B-Cell / Q000235:genetics*; D008875:Middle Aged; D051757:PAX5 Transcription Factor / Q000235:genetics*; D055815:Young Adult
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; C497239:IKZF1 protein, human; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D051740:Ikaros Transcription Factor