STEREOTYPED SUBSET #1 CHRONIC LYMPHOCYTIC LEUKEMIA: A DIRECT LINK BETWEEN BCR STRUCTURE, FUNCTION AND PATIENTS' PROGNOSIS

Chronic lymphocytic leukemia (CLL) with stereotyped B-cell receptor (BCR) belonging to subset #1 (IGHV1-5-7/IGKV1-39) display a poor outcome. To characterize their genetic and genomic features and BCR function, we selected 20 subset #1 CLL from a series of 579 cases. Subset #1 CLL, all showing unmutated IGHV, were associated with the presence of del(11q) (50%) in comparison with unmutated CLL, unmutated stereotyped CLL other than subset #1 and with cases utilizing the same IGHV genes but a heterogeneous VH CDR3 (non-subset #1 CLL). There were no distinctive features regarding CD38, ZAP-70 and TP53 disruption. NOTCH1, SF3B1 and BIRC3 were mutated in 15%, 0% and 5% of cases, respectively, while BIRC3 was deleted in 22% of cases. Microarray unsupervised analysis on 80 unmutated/mutated/stereotyped/non-stereotyped CLL showed a tight clustering of subset #1 cases. Their genomic signature exhibited several differentially expressed transcripts involved in BCR signal transduction, apoptosis regulation, cell proliferation and oxidative processes, regardless of del(11q). Accordingly, BCR ligation with anti-IgM revealed a significant higher proliferation of subset #1 vs. unmutated non-subset #1 CLL, both at baseline and after 24-48 hours stimulation. Subset #1 CLL represent a paradigmatic example of the direct link between BCR structure, function and patients prognosis