Abstract
Chronic lymphocytic leukemia (CLL) is highly heterogeneous, with extremely variable clinical course. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, specific immunophenotypic patterns and serum markers. The application of next-generation sequencing techniques has demonstrated the high genetic and epigenetic heterogeneity in CLL. The novel mutations could be pharmacologically targeted for individualized approach in some of the CLL patients. Potential neurogenic locus notch homolog protein 1 (NOTCH1) signalling targeting mechanisms in CLL include secretase inhibitors and specific antibodies to block NOTCH ligand/receptor interactions. In vitro studies characterizing the effect of the splicing inhibitors resulted in increased apoptosis of CLL cells regardless of splicing factor 3B subunit 1 (SF3B1) status. Several therapeutic strategies have been also proposed to directly or indirectly inhibit the toll-like receptor/myeloid differentiation primary response gene 88 (TLR/MyD88) pathway. Another potential approach is targeting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and inhibition of this prosurvival pathway. Newly discovered mutations and their signalling pathways play key roles in the course of the disease. This opens new opportunities in the management and treatment of CLL.
Highlights
Somatic mutations of immunoglobulin heavy variable (IGHV) gene occur in approximately half of Chronic lymphocytic leukemia (CLL) cases and are usually characteristic by more favourable prognosis. This contrasts with patients with unmutated CLL (IGHV gene sequences with a germline homology of 98% or higher), who have a more aggressive disease with worse prognosis [8,9]
The notch homolog protein 1 (NOTCH1) receptor acts as a ligand-activated transcription factor that directly transduces extracellular signals leading to changes in gene expression in the nucleus, including MYC, tumor protein p53 (TP53) and molecules of the nuclear factor (NF)-kB pathway [23,24,25]
The study conducted by Lopez-Guerra et al [40], suggested that DLL4 expressed by the tumor microenvironment activates NOTCH signaling in CLL
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The clinical heterogeneity of CLL reflects differences in the biology of the disease, including chromosomal alterations, gene mutations, specific immunophenotypic patterns and serum markers [3]. The novel, previously unknown, mutations which were revealed include neurogenic locus notch homolog protein 1 (NOTCH1), splicing factor 3B subunit 1 (SF3B1), tumor protein p53 (TP53), myeloid differentiation primary response gene 88 (MYD88), ataxia telangiectasia mutated (ATM), baculoviral IAP repeat containing 3 (BIRC3) and chromodomain-helicase-DNAbinding protein 2 (CHD2) [2,14,15,16,17] These recurrent somatic mutations were found to be involved in key cellular pathways, such as DNA damage response, cell cycle regulation, apoptosis, RNA metabolism, NOTCH signalling, nuclear factor (NF)-kB signalling, chromatin remodelling and inflammatory BCR pathways [2,14,15,16,17]. The consequent advances in understanding the clinical and biological heterogeneity of CLL and the development of new targeted therapies are leading us to an individualized, personalized approach [4]
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