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- Ghia, P., et al.
(författare)
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Early stages in the ontogeny of small B-cell lymphomas : genetics and microenvironment
- 2017
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 282:5, s. 395-414
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Tidskriftsartikel (refereegranskat)abstract
- In this review, we focus on the mechanisms underlying lymphomagenesis in chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and splenic marginal zone lymphoma. The cells of origin of these small B-cell lymphomas are distinct, as are the characteristic chromosomal lesions and clinical courses. One shared feature is retention of expression of surface immunoglobulin. Analysis of this critical receptor reveals the point of differentiation reached by the cell of origin. Additionally, the sequence patterns of the immunoglobulin-variable domains can indicate a role for stimulants of the B-cell receptor before, during and after malignant transformation. The pathways driven via the B-cell receptor are now being targeted by specific kinase inhibitors with exciting clinical effects. To consider routes to pathogenesis, potentially offering earlier intervention, or to identify causative factors, genetic tools are being used to track pretransformation events and the early phases in lymphomagenesis. These methods are revealing that chromosomal changes are only one of the many steps involved, and that the influence of surrounding cells, probably multiple and variable according to tissue location, is required, both to establish tumours and to maintain growth and survival. Similarly, the influence of the tumour microenvironment may protect malignant cells from eradication by treatment, and the resulting minimal residual disease will eventually give rise to relapse. The common and different features of the four lymphomas will be summarized to show how normal B lymphocytes can be subverted to generate tumours, how these tumours evolve and how their weaknesses can be attacked by targeted therapies.
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| 5. |
- Baliakas, Panagiotis, et al.
(författare)
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Recurrent mutations refine prognosis in chronic lymphocytic leukemia
- 2015
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 29, s. 329-336
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Tidskriftsartikel (refereegranskat)abstract
- Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.
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