title: BMI1, the polycomb-group gene, is recurrently targeted by genomic rearrangements in progressive B-cell leukemia/lymphoma.
abstract: BMI1, a Polycomb-group gene located at 10p12.2, is implicated in the pathogenesis of a variety of tumors. However, the genetic molecular mechanisms underlying its aberrant expression in cancer cells remain largely unknown. In this study, we show that BMI1 is recurrently targeted by chromosomal aberrations in B-cell leukemia/lymphoma. We identified a novel t(10;14)(p12;q32)/IGH-BMI1 rearrangement and its IGL variant in six cases of chronic lymphocytic leukemia (CLL) and found that these aberrations were consistently acquired at time of disease progression and high grade transformation of leukemia (Richter syndrome). The IG-BMI1 translocations were not associated with any particular molecular subtype of CLL and the leukemias were negative for common mutations of NOTCH1 and TP53, known to increase a risk of progression and transformation in CLL. In addition, using FISH and SNP array analysis, we identified a wide range of BMI1-involving 10p12 lesions in 17 cases of mantle cell lymphoma (MCL). These aberrations included various balanced and unbalanced structural abnormalities and very frequently but not exclusively, were associated with gain of the BMI1 locus and loss of the 10p terminal sequences. These findings point to genomic instability at the 10p region in MCL which likely promotes rearrangements and deregulation of BMI1. Our findings are in line with previously published observations correlating overexpression of BMI1 with tumor progression and chemoresistance. In summary, our study provides new insights into genetic molecular mechanisms underlying aberrant expression of BMI1 in lymphoma and documents its contribution in the pathogenesis of Richter syndrome and MCL.
authors.affiliation: Center for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Leila
authors.initials: L
authors.lastname: Rouhigharabaei
authors.forename: Julio Finalet
authors.initials: JF
authors.lastname: Ferreiro
authors.forename: Natalie
authors.initials: N
authors.lastname: Put
authors.forename: Lucienne
authors.initials: L
authors.lastname: Michaux
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.forename: Christine
authors.initials: C
authors.lastname: Lefebvre
authors.forename: Anne
authors.initials: A
authors.lastname: Gardiner
authors.forename: Wim
authors.initials: W
authors.lastname: De Kelver
authors.forename: Hilde
authors.initials: H
authors.lastname: Demuynck
authors.forename: Johan
authors.initials: J
authors.lastname: Verschuere
authors.forename: Ivan
authors.initials: I
authors.lastname: Théate
authors.forename: Carmen
authors.initials: C
authors.lastname: Vicente
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D022981:Allelic Imbalance; D002869:Chromosome Aberrations; D019938:Cyclin D1 / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D063150:Polycomb Repressive Complex 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014178:Translocation, Genetic
chemical_list: C069077:BMI1 protein, human; C530104:CCND1 protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019938:Cyclin D1; D063150:Polycomb Repressive Complex 1