BMI1, the Polycomb-Group Gene, Is Recurrently Targeted by Genomic Rearrangements in Progressive B-Cell Leukemia/Lymphoma.

Abstract 1099

Poster Board I-121

The 10p11 chromosomal site is recurrently affected by genomic abnormalities in B cell leukemia/lymphoma, but the molecular consequences of these aberrations remain unknown. We have collected three cases (2 female, 1 male; 67-69 years) of chronic lymphocytic leukemia (CLL) with a novel IGH-mediated t(10;14)(p11;q32) (#1 and 2) or its IGL variant t(10;22)(p11;q11) (#3), and one case of blastic mantle cell lymphoma (MCL) with a complex t(11;14)-positive karyotype including add(10)(p12) (#4). Case 1 showed unmutated VH genes and usage of VH3-21/D1-26/JH6. Cases 2 and 3 revealed mutated VH genes and usage of VH3-21/D1-14/JH4 and VH3-11/D4-4/JH6, respectively. In cases 1 and 2 with a monoallelic loss of RB1, the t(10;14)(p11,q32) was found as a secondary change at time of CLL progression/Richter transformation observed 148 and 50 months after diagnosis, respectively. In case 3, the sole t(10;22)(p11;q11) was identified at time of CLL diagnosis. All three patients died from disease progression 37-149 months after diagnosis. Of note, both patients with t(10;14) died from refractory disease 1 and 3 months after CLL progression/transformation and genetic detection f t(10;14). The patient #3 did not require therapy, but died from septic shock 37 months after diagnosis, and autopsy revealed diffuse and massive lymph node and spleen involvement. The patient with MCL (#4), 67 years old man with a previous history of prostatic adenocarcinoma and CLL, developed secondary central nervous system liesions and died 40 months after diagnosis of MCL. Extensive FISH studies of t(10;14) and t(10;22) mapped the 10p11 breakpoint in the region of the BMI1 locus. SNP array analysis of case 4 complemented by FISH identified amplification of the 10p11 region covering BMI1. Immunostaining with anti-BMI1 serum performed in 2 available cases (#2 and 3) showed expression of the BMI1 protein by neoplastic cells. This approach, however, did not allow to estimate whether the level of BMI1 expression in these cases was higher than in control CLL cases. BMI1 (B-cell-specific Moloney murine leukemia virus integration site 1) is a member of the Polycomb group of genes that are important epigenetic chromatin modifiers with an essential role in embryogenesis and the maintenance of adult stem cells. BMI1 was first identified as a protooncogene that cooperates with c-myc in the generation and development of mouse pre B-cell lymphomas. The BMI1 protein is a component of Polycomb repressive complex1 (PRC1), one of two multiprotein PRCs that maintain cell identity by gene suppression. The gene plays an important role in self-renewal of hematopoietic and neural stem cells. Multiple lines of evidence implicate BMI1 and other Polycomb genes in tumorigenesis. Among others, an aberrant expression of BMI1 has been observed in a wide spectrum of cancers and usually correlated with unfavourable clinical outcome. BMI1 is one of the genes marking the ABC-type signature of DLBCL, associated with a poor prognosis. High levels of BMI1 mRNA/protein were also detected in CLL, MCL, MM and HL. In some MCLs, overexpression of BMI1 correlated with genomic amplification of the BMI1 gene detected by aCGH in 12-24% of analysed cases (Jares and Campo, 2008). BMI1 has been shown to contribute to cell cycle regulation and senescence by acting as transcriptional repressor of the INK4a-ARF tumor suppressors. Despite the wealthy information on BMI1 contributing to a variety of tumors, molecular mechanisms underlying deregulation of BMI1 in neoplasms and functional consequences of these events remain elusive.

In summary, we show for the first time that BMI1, a postulated lymphoma-related oncogene, is recurrently targeted by IG-mediated chromosomal translocations in CLL and confirm its amplification in MCL. We found that in both cases with t(10;14)/IGH-BMI1, the translocation was acquired during clinical transformation of CLL initially harboring the del(13q)/RB1. The adverse prognostic impact of BMI1 aberrations in all four collected cases is reflected by a constantly aggressive clinical course of disease and short survival of the affected patients (1-50 months). In this regard, further molecular studies of the BMI1 pathway and its downstream partners are necessary to develop novel therapeutic approaches targeting this oncogene in human cancers.