High IGHV intraclonal diversification identifies CLL with good prognosis, features of anergy and specific T-cell profile

Chronic lymphocytic leukemia (CLL) with IGHV gene identity >=98% (U-CLL) experienced a worse prognosis respect to CLL with IGHV gene identity <98% (M-CLL). Moreover, CLL cells may exhibit ongoing mutations in IGHV genes, a phenomenon known as intraclonal diversification (ID). Through an original bioinformatic workflow for NGS data, we dichotomize cases with different ID levels into IDhigh and IDlow in CLL (n=983). Bioinformatic analysis of deconvoluted cell fractions from bulk RNASeq of IDlow, vs. IDhigh M-CLL (n=18) highlighted features of anergy in IDhigh M-CLL cells. When circumscribed to the T-cell component of IDhigh vs. IDlow M-CLL, bioinformatic analysis identified, both in CD8 and CD4 cell fractions of IDhigh M-CLL, an enrichment in T-cell activation pathways, induction of immunological synapsis-associated pathways and T-cell effectors functions.