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MAPK, WNT and AP-1 signaling pathways. In this con- text, preliminary results (data not shown) from our ongoing high-throughput study on aggressive CLL cases showed a great degree of consistency in the targeting of NCVs: the same “CLL-relevant” gene pathways were again among the most common targets of NCVs, further corroborating our present findings. Having said that, some of these vari- ants could represent bystander SHM targets of unknown significance or minor contributors to disease pathogenesis, therefore requiring further studies before definitive con- clusions can be drawn regarding their actual significance.
It is important to note that a recent study on the epige- netic profile of CLL48 reported a novel pathogenic role of TF dysregulation in CLL, with increased activity of EGR and NFAT as well as loss of EBF and AP-1, causing imbal- ances in the normal B-cell epigenetic program. Interestingly, certain members of these networks (e.g. EBF1, JUN and FOS) were among the most commonly affected TFs across all sample types tested. Collectively, our findings support the notion that gene pathways could be indirectly targeted by NCVs with the targets being either the genes themselves or other interacting genes, e.g. TFs.
Limitations of the present work involve the relatively small size of the cohort, mainly due to the rarity of sam- ples meeting the selection criteria. In particular, CLL patients had to have stable disease after a prolonged fol- low up, whereas all individuals with MBL had to have a persistent monoclonal B-cell population. Concerning LC- MBL, low CLL cell number was an additional challenging factor. Furthermore, although our targeted re-sequencing approach covered almost 50% of reported mutations in putative driver genes (as reported by Puente et al.),9 by def- inition this approach is not exhaustive.
In summary, we report that MBL and ultra-stable CLL are virtually indistinguishable at the genomic level. While this may be reflective of a passive and slow accumulation of mutations, we identified both exonic and NCV-targeted pathways central for B-cell biology and CLL development, likely linked to the acquisition of the MBL/CLL pheno- type. Importantly, ultra-stable CLL cases carried few known driver gene mutations, even after ten years of fol- low up, perhaps reflecting the central role of microenvi- ronmental signals rather than cell-intrinsic defects in shap- ing clonal behavior. In other words, cell-extrinsic trigger- ing, specifically mediated through the B-cell receptor, might represent the major driving force in the early stages of CLL, whereas disease progression will require acquisi- tion of genetic driver mutations.
Funding
This research project was supported by the Associazione Italiana per la Ricerca sul Cancro, AIRC (Investigator Grant #15189 to PG and Special Program Molecular Clinical Oncology – 5 per mille #9965), Milano, Italy, Ricerca Finalizzata 2010 (#2318823 to PG); Swedish Cancer Society, the Swedish Research Council, Uppsala University, Uppsala University Hospital, Lion’s Cancer Research Foundation, and Selander’s Foundation, Uppsala; and, H2020 “AEGLE, An analytics framework for integrated and personalized healthcare services in Europe”, by the European Union; “MEDGENET, Medical Genomics and Epigenomics Network” (No.692298) by the European Union; “GCH-CLL” funded by the General Secretariat for Research and Technology (GSRT) of Greece and the Italian Ministry of Health (MoH); and IMI2 “HARMO- NY”, funded by the European Union. AA is a fellow of Associazione Italiana per la Ricerca sul Cancro AIRC (Triennial fellowship “Guglielmina Lucatello é Gino Mazzega”).
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