Page 28 - 2020_09-Haematologica-web

J. Delgado et al.
wide association studies have identified up to 45 suscepti- bility loci, mostly mapping to non-coding regions of the genome.8 The mechanisms linking these susceptibility variants and the development of the disease are being elu- cidated thanks to integrated genome-wide association/ transcriptome/epigenome studies. These analyses recently revealed that 93% of the susceptibility loci are located in active promoters or enhancers and modify the binding sites of a number of transcription factors (e.g., FOX, NFAT and TCF/LEF) that, in turn, alter the expression of more than 30 genes involved in immune response, cell survival, or Wnt signaling (Figure 1).9 Despite these advances, molecular analysis for predisposition to CLL remains investigational.
Cell of origin
Hematopoietic stem cells derived from patients with CLL seem epigenetically primed to clonal expansions of CLL-like cells when implanted in mice. Interestingly, these clonal expansions do not always carry the same genomic aberrations as the original disease.10 Moreover, hematopoietic stem cells derived from patients with CLL express higher levels of transcription factors, such as TCF3, IKZF1 or IRF8, than those from healthy donors, which is intriguing if we consider that some susceptibility loci increase TCF3 binding or IRF8 expression.9 Mutations in driver genes such as NOTCH1 or SF3B1 may be acquired by hematopoietic stem cells, but also at more
advanced stages of B-cell differentiation, explaining why these genomic aberrations are frequently subclonal.11–13 These alterations observed in early steps of B-cell develop- ment are also consistent with the identification of shared mutations in CLL and myeloid cells and the detection of oligo- and multi-clonality in patients with MBL/CLL.14–16
The B-cell receptor (BCR) is crucial for CLL pathogene- sis and is composed of immunoglobulin (IG) molecules plus CD79a/b subunits. From an immunogenetic point of view, two major molecular subgroups have been identi- fied: those harboring unmutated IG heavy-chain variable region (IGHV) genes (U-CLL, ≥98% identity with the germline) and those with mutated IGHV genes (M- CLL).17,18 U-CLL originates from B cells that have not expe- rienced the germinal center, whereas M-CLL originates from post-germinal center B cells.19 In addition, around 30% of patients have highly homologous amino acid sequences derived from almost identical IG rearrange- ments, known as stereotypes.20 Several hundred stereo- types have been identified, of which 19 are considered major due to their frequency. The prognostic importance of several stereotypes has been prospectively validated.21 The presence of stereotypes and the remarkable bias in the use of certain IGHV genes highlight the relevance of antigen selection in CLL clonal expansion. Interestingly, the IG portion of the BCR may also recognize homotypic epitopes that trigger downstream signaling.22,23 In this sense, the acquisition of the mutation at position 110
Figure 1. Genetic susceptibility mechanisms. Most susceptibility loci map to non-coding regions of the genome, are mainly located in active promoters or enhancers, and modify the binding sites of a number of transcription factors. As a consequence, the binding sites for SPI1 and NF-κB are disrupted, whereas there is an increased affinity for members of the FOX, NFAT and TCF/LEF families. This, in turn, alters the expression of genes involved in the immune response (SP140, IRF8), cell survival (BCL2, BMF, CASP8, BCL2L11) or Wnt signaling (UBR5, LEF1).9
2206
haematologica | 2020; 105(9)