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Altered N-Linked Glycosylation in Follicular Lymphoma and Chronic Lymphocytic Leukemia: Involvement in Pathogenesis and Potential Therapeutic Targeting.

ABSTRACT: B-cell antigen receptor (BCR) expression is indispensable for survival of most B-cell malignancies. In follicular lymphoma (FL), N-linked glycosylation sites are introduced in the immunoglobulin (Ig) variable region genes. Oligosaccharides added to the acquired sites are unusually of the high-mannose type. These glycans interact with mannose-specific lectins, especially with dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). Lectin binding to FL triggers persistent activating signals, suggesting that lectins within the tumor microenvironment promote cell survival and proliferation. Insertion of N-glycosylation sites in Ig variable region genes has been detected in other germinal center-associated lymphomas, specifically in subsets of diffuse large B-cell lymphomas and Burkitt's lymphomas, suggesting involvement of altered glycans in pathogenesis of these malignancies as well. Furthermore, the BCR in chronic lymphocytic leukemia (CLL) carries high-mannose oligosaccharides, albeit in the heavy chain constant rather than variable region. The high expression level of the unique glycoform, particularly in the more aggressive unmutated CLL subset, suggests a functional significance for this glycan in CLL. As lectin interaction with the BCR is critical for FL and probably for some other lymphomas, targeting this interaction is considered to be an interesting therapeutic strategy. Reagents for blockade of lectin-BCR interaction may include antibodies against high-mannose glycans and mannose-based oligosaccharide mimics or non-carbohydrate glycomimetics. Moreover, as this interaction triggers signaling pathways similar to those demonstrated for BCR engagement by antigen, BCR signal transduction inhibitors may emerge as effective therapeutics for lectin-driven malignancies.

SUBMITTER: Hollander N

PROVIDER: S-EPMC5539419 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:BACKGROUND: Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). Over time, however, virtually all CLL patients become fludarabine-refractory. To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria. RESULTS: By comparing the expression profiles of these two groups of patients, we identified a microRNA signature able to distinguish refractory from sensitive CLLs. The expression of some microRNAs was also able to predict fludarabine resistance of 12 independent CLL patients. Among the identified microRNAs, miR-148a, miR-222 and miR-21 exhibited a significantly higher expression in non-responder patients either before and after fludarabine treatment. After performing messenger RNA expression profile of the same patients, the activation of p53-responsive genes was detected in fludarabine responsive cases only, therefore suggesting a possible mechanism linked to microRNA deregulation in non-responder patients. Importantly, inhibition of miR-21 and miR-222 by anti-miRNA oligonucleotides induced a significant increase in caspase activity in fludarabine-treated p53-mutant MEG-01 cells, suggesting that miR-21 and miR-222 up-regulation may be involved in the establishment of fludarabine resistance. CONCLUSIONS: This is the first report that reveals the existence of a microRNA profile that differentiate refractory and sensitive CLLs, either before and after fludarabine mono-therapy. A p53 dysfunctional pathway emerged in refractory CLLs and could contribute in explaining the observed miRNA profile. Moreover, this work indicates that specific microRNAs can be used to predict fludarabine resistance and may potentially be used as therapeutic targets, therefore establishing an important starting point for future studies.

Project description:BackgroundExportin 1 (XPO1/CRM1) is a key mediator of nuclear export with relevance to multiple cancers, including chronic lymphocytic leukemia (CLL). Whole exome sequencing has identified hot-spot somatic XPO1 point mutations which we found to disrupt highly conserved biophysical interactions in the NES-binding groove, conferring novel cargo-binding abilities and forcing cellular mis-localization of critical regulators. However, the pathogenic role played by change-in-function XPO1 mutations in CLL is not fully understood.MethodsWe performed a large, multi-center retrospective analysis of CLL cases (N = 1286) to correlate nonsynonymous mutations in XPO1 (predominantly E571K or E571G; n = 72) with genetic and epigenetic features contributing to the overall outcomes in these patients. We then established a mouse model with over-expression of wildtype (wt) or mutant (E571K or E571G) XPO1 restricted to the B cell compartment (Eµ-XPO1). Eµ-XPO1 mice were then crossed with the Eµ-TCL1 CLL mouse model. Lastly, we determined crystal structures of XPO1 (wt or E571K) bound to several selective inhibitors of nuclear export (SINE) molecules (KPT-185, KPT-330/Selinexor, and KPT-8602/Eltanexor).ResultsWe report that nonsynonymous mutations in XPO1 associate with high risk genetic and epigenetic features and accelerated CLL progression. Using the newly-generated Eµ-XPO1 mouse model, we found that constitutive B-cell over-expression of wt or mutant XPO1 could affect development of a CLL-like disease in aged mice. Furthermore, concurrent B-cell expression of XPO1 with E571K or E571G mutations and TCL1 accelerated the rate of leukemogenesis relative to that of Eµ-TCL1 mice. Lastly, crystal structures of E571 or E571K-XPO1 bound to SINEs, including Selinexor, are highly similar, suggesting that the activity of this class of compounds will not be affected by XPO1 mutations at E571 in patients with CLL.ConclusionsThese findings indicate that mutations in XPO1 at E571 can drive leukemogenesis by priming the pre-neoplastic lymphocytes for acquisition of additional genetic and epigenetic abnormalities that collectively result in neoplastic transformation.

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Altered N-Linked Glycosylation in Follicular Lymphoma and Chronic Lymphocytic Leukemia: Involvement in Pathogenesis and Potential Therapeutic Targeting.

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