Abstract
AbstractGenetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). However, scant data are available on preferential associations between specific genetic alterations and stereotyped BCR subsets. By analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched in specific molecular alterations influencing disease course. SF3B1 mutations are the genetic hallmark of IGHV3-21-CLL belonging to subset 2 (52%) but are evenly represented in nonstereotyped IGHV3-21-CLL. Trisomy 12 (87%) and NOTCH1 mutations (62%) characterize IGHV4-39-CLL belonging to subset 8 but occur with the expected frequency in IGHV4-39-CLL with heterogeneous BCR. Clinically, co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, +12, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome.
Highlights
chronic lymphocytic leukemia (CLL) often carries surface B-cell receptor (BCR) with similar stereotypic patterns resulting from IGHV-IGHD-IGHJ rearrangements already present in the natural B-cell repertoire of normal individuals prior to transformation, suggesting that recognition of common epitopes or classes of structurally similar epitopes is likely involved in leukemic clone selection.[9,10,11,12]
To uncover the interactions between molecular lesions of cancer genes and BCR-driven mechanisms in CLL, we performed a crosssectional investigation of the associations between the most recurrent mutations (TP53, NOTCH1, SF3B1, BIRC3, and MYD88), chromosomal abnormalities, and BCR features in 1419 newly presented CLL cases
IGHV-unmutated CLL showed a broad association with all unfavorable genetic lesions, expression of zeta-chain-associated protein kinase 70 and CD38, 2 molecules that may cooperate with the BCR in CLL,[1] appeared to cluster with specific genetic subgroups
Summary
Genetic lesions and B-cell receptor (BCR) signaling are both oncogenic drivers in chronic lymphocytic leukemia (CLL). BCR subsets 2 and 8 show associations between specific genetic alterations and stereotyped BCR subsets. By specific genetic profiles analyzing 1419 cases, 2 CLL subsets (2 and 8) harboring stereotyped BCR are enriched influencing CLL course. Co-occurrence of SF3B1 mutations and subset 2 BCR configuration prompts disease progression in IGHV3-21-CLL, whereas cooperation between NOTCH1 mutations, 112, and subset 8 BCR configuration invariably primes CLL transformation into Richter syndrome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome. These findings provide a proof of concept that specific stereotyped BCR may promote or select molecular lesions influencing outcome. (Blood. 2013;121(24):4902-4905)
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