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Characterization of specific enhancer RNAs involved in ibrutinib resistance mechanism in marginal zone lymphoma



Napoli N.



Marginal zone lymphoma (MZL) accounts for approximately 10% of all B-cell lymphomas, and comprise three entities with specific diagnostic criteria, different behavior and therapeutic implications: the extranodal MZL of MALT type (MALT lymphoma), the splenic MZL (SMZL), and the nodal MZL (NMZL). Although they present specific alterations that can be used for their differential diagnosis, the three MZLs largely share common lesions and deregulated pathways. There is no clear consensus for the treatment of patients with disseminated marginal zone lymphoma. Most of the available data come from phase II studies with a limited number of patients and short follow-up. The therapeutic options include chemotherapy, rituximab alone or rituximab with chemotherapy. Several small molecules have also been now evaluated in phase II studies. The current proposed project will focus on ibrutinib, the first in class BTK inhibitor approved by FDA for the treatment of relapsing MZL patients. As for any anti-cancer drug, resistance is an issue also for this compound. We generated a model of secondary resistance to ibrutinib derived from the MZL VL51 cell line. We have detected overexpression of PI3K signaling and proliferation signatures in the ibrutinib-resistant cell line at RNA level but no somatic mutations linked with resistance at whole exome sequencing. Even though genetic clonal evolution in cancer cells plays a central role in mediating resistance to targeted and conventional therapies, mutations often cannot be identified or cannot explain the mechanism of drug resistance. Stable non-genetic resistance can be acquired by dynamic transcriptional adaptation, as recently shown for clinical resistance to BET inhibitors in AML. Enhancers are key regulators of transcriptional program during cell differentiation but they can also be involved in the adaptation that malignant cells need to evade therapeutic challenge. Stable non-genetic resistance is not due to selection of a pre-existing clone but it is a compensatory mechanism by which inherently plastic cancer cells activate alternative pattern of enhancers to sustain the expression of key survival genes, as stem cells make to differentiate to lineage specific cells. The reprogramming induced to develop drug resistance is a stable epigenetic adaptation which cannot be reverted by the drug suspension. Most active enhancers are also transcribed in long noncoding RNAs (lncRNAs) molecules called enhancer RNAs (eRNAs). They play a regulatory role sustaining the correct chromatin conformation required to transactivate promoters controlled by the enhancer. eRNAs can occasionally be stabilized and acquire the capability to act in trans regulating also distal loci. Those lncRNAs may become relevant regulatory tools for the biology of cancer cells. We have functionally characterized a germinal center-specific eRNA involved in the pathogenesis of diffuse large B cell lymphoma, in which it regulates proliferation and differentiation coordinating the interplay of fundamental transcriptional pathways.

Additional information

Start date
End date
18 Months
Funding sources
Swiss National Science Foundation / Spark