Novel Mechanisms of Regulation of miRNAs in CLL

Balatti, Veronica; Acunzo, Mario; Pekarky, Yuri; Croce, Carlo M.

doi:10.1016/j.trecan.2016.02.005

Cited by 36 publications

(32 citation statements)

References 71 publications

(117 reference statements)

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“…Bonci et al (2008) showed that CCND1 and WNT3A are targets of this cluster and forced expression induced growth arrest and apoptosis. Anti-apoptotic genes (BCL-2, Activin A and CCND1) (Bonci et al, 2008;Li et al, 2013a;Bufalino et al, 2015) and pro-apoptotic genes (p53, BIM and Caspase-7) (Tang et al, 2013;Balatti et al, 2016;Robaina et al, 2016) are often targets of miRNA clusters and are important for inhibiting apoptosis. miR-106b/25 is significantly upregulated in prostate cancer and shows resistance to apoptosis by targeting CASP7 (Hudson et al, 2013).…”

Section: (4) Cell Cycle Progressionmentioning

confidence: 99%

Clustered miRNAs and their role in biological functions and diseases

et al. 2018

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MicroRNAs (miRNAs) are endogenous, small non-coding RNAs known to regulate expression of protein-coding genes. A large proportion of miRNAs are highly conserved, localized as clusters in the genome, transcribed together from physically adjacent miRNAs and show similar expression profiles. Since a single miRNA can target multiple genes and miRNA clusters contain multiple miRNAs, it is important to understand their regulation, effects and various biological functions. Like protein-coding genes, miRNA clusters are also regulated by genetic and epigenetic events. These clusters can potentially regulate every aspect of cellular function including growth, proliferation, differentiation, development, metabolism, infection, immunity, cell death, organellar biogenesis, messenger signalling, DNA repair and self-renewal, among others. Dysregulation of miRNA clusters leading to altered biological functions is key to the pathogenesis of many diseases including carcinogenesis. Here, we review recent advances in miRNA cluster research and discuss their regulation and biological functions in pathological conditions.

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Section: (4) Cell Cycle Progressionmentioning

confidence: 99%

Clustered miRNAs and their role in biological functions and diseases

et al. 2018

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“…≤ 0.05) were analyzed with DASHR and UCSC human genome browser for sequence annotations. Five of the novel miRs (novelmiR_4291, novelmiR_1520, novelmiR_1559, novelmiR_1732 and novelmiR_4370) showed homology with a multitude of tRNA molecules located on chromosomes 1,6,7,9,11,12,14,15,16, and 17 (supplementary table 1). The novelmiR_4370 showed homology with a piRNA-36225 (alias piRNA-28374; GenBank: DQ598159.1) as well.…”

Section: Annotation Of Novel Mirsmentioning

confidence: 99%

“…In the landmark study of Calin et al, a 13 miR signature was reported in CLL patients with high Zeta-chain-associated protein kinase 70 (ZAP70) expression and unmutated immunoglobulin heavy chain variable region gene (IGHV) status 6 . Differential expression of various miRNAs including miR-15a, miR-16, miR-29a/b/c, miR-223 and miR-150 have been consistently reported to be associated with well established prognostic factors such as IGHV status, ZAP70/ CD38 expression, β2 microglobulin levels and disease progression in CLL 11 . A few studies have identified karyotype specific miR signatures in CLL that could discriminate patients harboring del(17p), del(11q), del(13q), trisomy 12, and normal karyotype 12,13 .…”

Section: Introductionmentioning

confidence: 99%

RNA-Seq profiling of deregulated miRs in CLL and their impact on clinical outcome

et al. 2020

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Abnormal expression patterns of regulatory small non-coding RNA (sncRNA) molecules such as microRNAs (miRs), piwi-interacting RNAs (piRNAs), and small nucleolar RNAs (snoRNAs) play an important role in the development and progression of cancer. Identification of clinically relevant sncRNA signatures could, therefore, be of tremendous translational value. In the present study, genome-wide small RNA sequencing identified a unique pattern of differential regulation of eight miRs in Chronic Lymphocytic Leukemia (CLL). Among these, three were up-regulated (miR-1295a, miR-155, miR-4524a) and five were down-regulated (miR-30a, miR-423, miR-486*, let-7e, and miR-744) in CLL. Altered expression of all these eight differentially expressed miRs (DEMs) was validated by RQ-PCR. Besides, seven novel sequences identified to have elevated expression levels in CLL turned out to be transfer RNA (tRNA)/piRNAs (piRNA-30799, piRNA-36225)/snoRNA (SNORD43) related. Multivariate analysis showed that miR-4524a (HR: 1.916, 95% CI: 1.080-3.4, p value: 0.026) and miR-744 (HR: 0.415, 95% CI: 0.224-0.769, p value: 0.005) were significantly associated with risk and time to first treatment. Further investigations could help establish the scope of integration of these DEM markers into risk stratification designs and prognostication approaches for CLL.

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“…14 They mediate the deacetylation and demethylation of lysine residues (H3K9/14 and H3K4me3) on histones to silence genes, 15,16 and in CLL, they have been shown to silence the expression of key microRNA genes (miRNAs or miRs) and miRs such as miR-15a, miR-16, miR-29b, and miR-106b. 17,18 However, the role of miRs in targeting BTK, their expression levels in CLL, and the role of HDACs in dysregulating the BTK-targeting miRs are unknown.…”

Section: Introductionmentioning

confidence: 99%

Targeting BTK through microRNA in chronic lymphocytic leukemia

Bottoni

Rizzotto

Lai

et al. 2016

Blood

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Key Points• Inhibition of HDAC reverses epigenetic silencing to upregulate miRs that target BTK and suppress its downstream prosurvival signaling.• We identified a rationale for the dual targeting of BTK when combined with ibrutinib and a strategy to eliminate the C481S-mutant BTK clone.Bruton's tyrosine kinase (BTK) is a critical mediator of survival in B-cell neoplasms. Although BTK inhibitors have transformed therapy in chronic lymphocytic leukemia (CLL), patients with high-risk genetics are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of microRNAs (miRs) that target BTK in primary CLL cells and show that the histone deacetylase (HDAC) repressor complex is recruited to these miR promoters to silence their expression. Targeting the HDACs by using either RNA interference against HDAC1 in CLL or a small molecule inhibitor (HDACi) in CLL and mantle cell lymphoma restored the expression of the BTK-targeting miRs with loss of BTK protein and downstream signaling and consequent cell death. We have also made the novel and clinically relevant discovery that inhibition of HDAC induces the BTK-targeting miRs in ibrutinib-sensitive and resistant CLL to effectively reduce both wild-type and C481S-mutant BTK. This finding identifies a novel strategy that may be promising as a therapeutic modality to eliminate the C481S-mutant BTK clone that drives resistance to ibrutinib and provides the rationale for a combination strategy that includes ibrutinib to dually target BTK to suppress its prosurvival signaling. (Blood. 2016;128(26):3101-3112)

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Novel Mechanisms of Regulation of miRNAs in CLL

Cited by 36 publications

References 71 publications

Clustered miRNAs and their role in biological functions and diseases

Clustered miRNAs and their role in biological functions and diseases

RNA-Seq profiling of deregulated miRs in CLL and their impact on clinical outcome

Targeting BTK through microRNA in chronic lymphocytic leukemia

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