BIRC3 disruption in CLL. (A) prevalence of BIRC3 disruption in clinical MBL, in CLL at diagnosis, in fludarabine-refractory CLL, in fludarabine-sensitive CLL, and in RS. Numbers on top indicate the actual number of mutated samples over the total number analyzed. (B) Schematic diagram of the BIRC3 protein with its key functional domains. Color-coded symbols indicate the type and position of the mutations in BIRC3. (C) Graphic representation of segmentation data from 4 CLL patients carrying BIRC3 deletion. Deletions start from a centromeric break that truncates BIRC3 and removes its terminal exons, including exon 9, which encodes the RING domain. Sample 09-361 harbors a focal loss of 411 kb on 11q22 involving BIRC3 and its homolog, BIRC2. Each track represents one sample; white denotes a normal (diploid) copy number and blue indicates region of a copy number loss (Integrative Genomics Viewer software; http//www.broadinstitute.org/igv; assembly NCBI36/hg18). Individual genes in the region are aligned in the bottom panel. Dual-color FISH validates the occurrence of 11q22 deletion involving BIRC3 but sparing ATM in sample 09-361 (RP11-177O8-BIRC3 specific probe in green and LSIATM probe in orange). (D) Mutual relationship of the BIRC3 disruption with other genetic lesions in CLL at diagnosis and in fludarabine-refractory CLL. In the heat map, rows correspond to identical genes and columns represent individual patients color-coded based on the gene status (white indicates wild-type and red, mutations and/or deletion of TP53, mutations and/or deletion of BIRC3, mutations of SF3B1, and mutations of NOTCH1).