Integrated Genomic Profiling of Chronic Lymphocytic Leukemia Identifies Subtypes of Deletion 13q14

Abstract

Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness with a variable clinical course. Loss of chromosomal material on chromosome 13 at cytoband 13q14 is the most frequent genetic abnormality in CLL, but the molecular aberrations underlying del13q14 in CLL remain incompletely characterized. We analyzed 171 CLL cases for loss of heterozygosity and subchromosomal copy loss on chromosome 13 in DNA from fluorescence-activated cell sorting-sorted CD19 + cells and paired buccal cells using the Affymetrix XbaI 50k SNP array platform. The resulting highresolution genomic maps, together with array-based measurements of expression levels of RNA in CLL cases with and without del13q14 and quantitative PCR-based expression analysis of selected genes, support the following conclusions: (a) del13q14 is heterogeneous and composed of multiple subtypes, with deletion of Rb or the miR15a/miR16 loci serving as anatomic landmarks, respectively; (b) del13q14 type Ia deletions are relatively uniform in length and extend from breakpoints close to the miR15a/miR16 cluster to a newly identified telomeric breakpoint cluster at the f50.2 to 50.5 Mb physical position; (c) LATS2 RNA levels are f2.6-fold to 2.8-fold lower in cases with del13q14 type I that do not delete Rb, as opposed to del13q14 type II or all other CLL cases; (d) PHLPP RNA is absent in f50% of CLL cases with del13q14; and (e) f15% of CLL cases display marked reductions in miR15a/miR16 expression that are often but not invariably associated with bi-allelic miR15a/miR16 loss. These data should aid future investigations into biological differences imparted on CLL by different del13q14 subtypes.

Role of miR-15/16 in CLL

“…35 Interestingly, in addition to miR-15/16, this region also contained DLEU7 gene (that was previously identified as a candidate tumor-suppressor gene at 13q14) located telometic to miR-15/16. 35, 36 We investigated whether DLEU7 can also function as a tumor suppressor and cooperate with miR-15/16, 37 as DLEU7 is the only protein-coding gene located within reported deleted region.…”

Chronic lymphocytic leukemia: Time to go past genomics?

“…This suggests that DLEU2 have specific function, beside MIR15A/16-1. In addition, the loss of other genetic elements in the vicinity of the human MDR may also participate to CLL pathogenesis and severity [118]. Subsequent works have further investigated the involvement of miRNAs in CLL, associating patterns of expression with clinical features [119].…”

13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia

“…Type II 13q deletions are defined by deletion of RB1, as described by Ouilette et al 17 and have previously been found to be enriched in patients who received treatment or had a higher clinical stage. 17 Therefore, 13q deletion types were assigned to our cases.…”

“…15,16 It has been proposed that 13q deletions could be categorized into two types; Type I deletions target a region including the MDR, whereas larger Type II deletions include the RB1 locus and were enriched in treated patients and those with higher Rai stage. 17 The significance of large 13q deletions and RB1 in particular, is further emphasized by their association with elevated genome complexity. 18 It is likely that the biological consequence of a unique deletion anatomy is complex, resulting in the disruption of multiple regulatory sequences.…”