Stereotyped subset #1 chronic lymphocytic leukemia: a direct link between B‐cell receptor structure, function, and patients' prognosis

Abstract

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 using 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 versus unmutated non-subset #1 CLL, both at baseline and after 24-48 hr stimulation. Subset #1 CLL represent a paradigmatic example of the direct link between BCR structure, function, and patients prognosis.

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

“…10,[15][16][17][18][19][20][21][22][23][24][25] In addition, preliminary observations in CLL, in relatively small patient series, suggest that the frequency and patterns of mutations within several genes, namely, NOTCH1, SF3B1 and TP53, may differ amongst subsets of patients carrying stereotyped BcRs, the paradigmatic example being the recently observed enrichment of SF3B1 mutations in the clinically aggressive subset #2. [26][27][28] With this in mind, we sought to systematically evaluate the mutational status of BIRC3, MYD88, NOTCH1, SF3B1 and TP53 in 565 CLL patients assigned to one of 10 major stereotyped subsets, and representing cases with varying SHM status, i.e.…”

Distinct immunoglobulin heavy chain variable region gene repertoire and lower frequency of del(11q) in Taiwanese patients with chronic lymphocytic leukaemia

“…These also supported an ethnicity‐dependent association of IGHV usage. In addition, previous studies showed that stereotyped BCRs were of prognostic relevance: subset 1 or 2 was associated with poor outcome in the Western studies (Maura et al , ; Strefford et al , ; Baliakas et al , ; Del Giudice et al , ), whereas patients with subset 4 might not require treatment (Rani et al , ). Both the present study and that reported by Marinelli et al () observed that patients with subset 8 had an unfavourable survival.…”

Somatic Hypermutational Status and Gene Repertoire of Immunoglobulin Rearrangements in Chronic Lymphocytic Leukemia

“…Subset#1(IGHV1/5/7/IGKV1(D)-39)isthesecondlargeststereotypedsubset,mostlyunmutated, and also associated with aggressive disease and adverse prognosis. Recent studies revealedasignificantenrichmentforTP53defects(del17pand/orTP53mutations),trisomy 12q and NOTCH1 mutations [128,130]. In addition, subset #1 B cells exhibited higher proliferation rate following in vitro BCR ligation with anti-IgM antibodies than non-subset #1 unmutated B cells [130].…”

“…Recent studies revealedasignificantenrichmentforTP53defects(del17pand/orTP53mutations),trisomy 12q and NOTCH1 mutations [128,130]. In addition, subset #1 B cells exhibited higher proliferation rate following in vitro BCR ligation with anti-IgM antibodies than non-subset #1 unmutated B cells [130]. Similarly to subset #2, cases assigned to subset #1 have worse prognosis when compared to unclustered cases using the same IGHV genes [82,85,130].…”