LINC00152 is a lncRNA modulated by microenvironmental stimuli that has pathogenetic and clinical relevance in CLL

Abstract

Abstract Chronic lymphocytic leukemia (CLL) is a common lymphoid neoplasm with heterogeneous biological features and clinical behavior, influenced by acquired genetic alterations and microenvironment interactions. We explored non-coding RNAs expression to understand their role in CLL pathogenesis and identify new clinically relevant biological biomarkers that could improve CLL prognosis and management. We initially profiled coding and non-coding RNA families in different CLL cohorts (N = 21) to identify those modulated by a combination of agonist microenvironment stimuli. Then we focused on lncRNAs that were overexpressed in response to the agonist stimuli, even in the presence of Ibrutinib, and whose baseline expression was associated with a shorter time-to-treatment in an independent CLL series (N = 266). Three lncRNAs ( LINC00152 , LINC00158 and RP11-161H23.5 ) were selected for functional validations in MEC-1 CLL cell line, where they demonstrated to regulate genes and pathways activated by microenvironmental stimuli, including induction of miR-155, a key oncomiR also enhanced by agonist treatment. LINC00152 expression was associated with proxies of microenvironment stimulation in vivo, and its silencing ex vivo reduced cell growth under combined microenvironmental stimulation and Ibrutinib in a subset of Ibrutinib-relapsed primary CLL samples, underscoring its potential relevance for further studies to improve CLL therapy.