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Editorials
Another step forward in the 20-year history of IGHV mutations in chronic lymphocytic leukemia
Ilaria Del Giudice and Robin Foà
Hematology, Department of Translational and Precision Medicine, ‘Sapienza’ University, Rome, Italy E-mail: rfoa@bce.uniroma1.it
doi:10.3324/haematol.2018.207399
Chronic lymphocytic leukemia (CLL) derives from the expansion of clonal and antigen-experienced mature B lymphocytes, whose accumulation results from a dynamic imbalance between cell death and prolifer- ation. The former is impaired by the overexpression of the anti-apoptotic protein BCL2 by CLL cells and the latter is mainly driven by the B-cell receptor (BCR), the key mole- cule to elucidate the pathogenic and evolution mechanisms of the disease.
Chronic lymphocytic leukemia is a highly heterogeneous disease both in terms of biological landscape and clinical course, including the interval from diagnosis to first pro- gression requiring treatment (time-to-first-treatment, TTFT), the degree and duration of response to therapy, overall survival (OS), and risk of transformation into an aggressive lymphoma (Richter’s syndrome). The prognosis of CLL patients can be accurately defined by combining clinical and biological parameters that include BCR features, cytogenetic lesions, immunophenotypic markers, and gene mutations. Some biomarkers are also useful predictors of response to therapy.
Mutations of the genes codifying for the immunoglobulin heavy chain variable region (IGHV) of the BCR represent one of the most robust prognostic biomarkers, and, indeed, was one of the first to be identified. IGHV mutations never change over time, and thus represent the fingerprint of the disease. Back in 1999, it was reported that CLL patients with mutated IGHV genes (M-CLL) (i.e. <98% cut-off of IGHV identity to the germline counterpart) display a longer TTFT and a longer survival than CLL with unmutated IGHV genes (U-CLL) (≥98%).1,2 The subsequent identifica- tion in about 30% of CLL of stereotyped BCRs was even more intriguing.3,4 Stereotyped BCRs (namely those with a nearly identical length of the HCDR3 region, shared amino acids in key positions and the non-stochastic pairing of IGHV and light chain genes) identify subgroups defined “subsets”. More frequent in U-CLL (40%) than in M-CLL (10%) in Caucasians, CLL subsets display distinctive clini- co-biological associations: subset #4, mostly M-CLL, is associated to a young age at diagnosis and an indolent dis- ease; subset #1, U-CLL, to a very aggressive clinical course; subset #8, U-CLL, to a higher risk of developing Richter’s syndrome; subset #2 to a poor prognosis regardless of the percentage of IGHV mutations.5 Although the IGHV gene usage and the frequency of BCR subsets can vary across populations with a different incidence of CLL (i.e. Caucasian vs. Chinese), it is interesting that these clinico- biological associations hold true across all ethnic groups.6
In 2015, the value of the IGHV status in predicting the outcome after chemoimmunotherapy also emerged, since M-CLL patients have a significantly longer progression-free survival (PFS), particularly when devoid of poor-risk fluo-
rescence in situ hybridization (FISH) lesions.7 In contrast, it became apparent that the IGHV status does not influence
8,9
the efficacy of the BTK inhibitor ibrutinib. Thus, it has
been suggested that both the IGHV status and TP53 dele- tions/mutations should be investigated at the time of dis- ease progression in order to guide the first-line therapeutic choice between chemoimmunotherapy and novel agents.10 Given the clinical implications, the European Research Initiative on CLL (ERIC) group has conducted an interna- tional harmonization process across labs for the analysis and reporting of IGHV and TP53 genes in CLL, and this has led to the recently up-dated recommendations.11,12
Although the pathogenic mechanisms operational in CLL are far from being fully elucidated, the oncogenic function of the BCR is indirectly demonstrated by the high anti- leukemic efficacy of kinase inhibitors that block BCR sig- naling (i.e. ibrutinib, idelalisib, acalabrutinib, duvelisib). On the one hand, in CLL, unlike other lymphoproliferative dis- eases, the BCR is capable of generating a cell-autonomous signaling driven by the interactions between HCDR3 of near BCR (BCR-BCR) on the cell surface.13 On the other hand, the quality of BCR signaling is heterogeneous: U-CLL are more responsive in vitro to IgM ligation in terms of mod- ulation of the gene expression profile, advance in the cell cycle, and increase in proliferation compared to M-CLL.14 As for a commonly accepted model, U-CLL show a weak autonomous BCR-BCR signaling, a low affinity binding to auto-antigens, an increased BCR responsiveness, and an aggressive clinical course, while M-CLL patients show a strong autonomous BCR-BCR signaling that leads to an anergic state, a lower proliferative response after BCR stim- ulus, and an overall indolent course.15,16 This model concili- ates a shared pathogenic mechanism with the biological and clinical heterogeneity of CLL. In addition, BCR stereo- typing likely supports the role of an antigenic pressure in the selection of the leukemic clone.3-5 Among the various factors that contribute to modulate the BCR responsive- ness, the microenvironment certainly has a relevant role, since the CLL cells within the lymph node show an upreg- ulation of genes involved in BCR signaling and NfKB acti- vation, at variance from the circulating CLL cells from the same individual.17
Although the mechanisms driving the heterogeneity of CLL genetics are currently unknown, since leukemia kinet- ics and genetic complexity are usually closely related, it would seem that the BCR can play a role in maintaining genetic stability or in acquiring genetic instability in CLL. Indeed, U-CLL and M-CLL display a variable proportion of the different genetic lesions, as well as of the BCR subsets; U-CLL is enriched with biomarkers with an adverse prog- nostic significance, although not exclusively.
In the present issue of Haematologica, on behalf of the
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