miRNAs as cornerstones in chronic lymphocytic leukemia pathogenesis and therapeutic resistance– An emphasis on the interaction of signaling pathways

Siegel, 2021, Cancer Statistics, 2021, CA Cancer J. Clin., 71, 7, 10.3322/caac.21654 Hallek, 2021, Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures, Am. J. Hematol., 96, 1679, 10.1002/ajh.26367 Hallek, 2018, iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL, Blood, 131, 2745, 10.1182/blood-2017-09-806398 Yamamoto, 2008, Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002, Cancer Causes Control, 19, 10.1007/s10552-007-9097-2 Yang, 2021, Ethnic and geographic diversity of chronic lymphocytic leukaemia, Leukemia, 35, 433, 10.1038/s41375-020-01057-5 Alaggio, 2022, The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms, Leukemia, 36, 1720, 10.1038/s41375-022-01620-2 Campo, 2022, The International consensus classification of mature lymphoid neoplasms: a report from the clinical advisory committee, Blood, 140, 1229, 10.1182/blood.2022015851 Hallek, 2019, Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment, Am. J. Hematol., 94, 1266, 10.1002/ajh.25595 Calin, 2009, Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes, Blood, 114, 10.1182/blood-2009-07-192740 Hallek, 2021, Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures, Am. J. Hematol., 96, 1679, 10.1002/ajh.26367 Jakšić, 2018, Guidelines for diagnosis and treatment of chronic lymphocytic leukemia. Krohem B-Cll 2017, Acta Clin. Croat., 57, 190, 10.20471/acc.2018.57.01.27 Hadi, 2022, miR-574, miR-499, miR-125b, miR-106a, and miR-9 potentially target TGFBR-1 and TGFBR-2 genes involving in inflammatory response pathway: Potential novel biomarkers for chronic lymphocytic leukemia, Pathol. - Res. Pract., 238, 10.1016/j.prp.2022.154077 Rodriguez, 2004, Identification of mammalian microRNA host genes and transcription units, Genome Res, 14, 10.1101/gr.2722704 Doghish, 2023, miRNAs insights into rheumatoid arthritis: Favorable and detrimental aspects of key performers, Life Sci., 314, 10.1016/j.lfs.2022.121321 Ismail, 2023, miRNAs as cornerstones in diabetic microvascular complications, Mol. Genet. Metab., 138, 10.1016/j.ymgme.2022.106978 Abulsoud, 2023, Mutations in SARS-CoV-2: Insights on structure, variants, vaccines, and biomedical interventions, Biomed. Pharmacother., 157, 10.1016/j.biopha.2022.113977 Ismail, 2022, Clinical and chest computed tomography features of patients suffering from mild and severe COVID-19 at Fayoum University Hospital in Egypt, Plos One, 17, 10.1371/journal.pone.0271271 Doghish, 2021, Clinical characteristics of Egyptian male patients with COVID‐19 acute respiratory distress syndrome, Plos One, 16, 10.1371/journal.pone.0249346 El-Mahdy, 2023, miRNAs role in bladder cancer pathogenesis and targeted therapy: signaling pathways interplay-a review, Pathol. -Res. Pract., 10.1016/j.prp.2023.154316 El-Mahdy, 2022, miRNAs inspirations in hepatocellular carcinoma: detrimental and favorable aspects of key performers, Pathol. Res. Pract., 10.1016/j.prp.2022.153886 Matis, 2022, MiR-146b-5p regulates IL-23 receptor complex expression in chronic lymphocytic leukemia cells, Blood Adv., 6, 5593, 10.1182/bloodadvances.2021005726 Huang, 2023, Target-induced multiple palindrome-mediated strand displacement amplification of Scarecrow-shaped DNA nanoprobe for ultrasensitive detection of MicroRNA, Sens. Actuators B Chem., 376, 10.1016/j.snb.2022.133003 Li, 2023, Defining disease-related modules based on weighted miRNA synergistic network, Comput. Biol. Med., 152, 10.1016/j.compbiomed.2022.106382 Grenda, 2022, Inside the chronic lymphocytic leukemia cell: miRNA and chromosomal aberrations, Mol. Med. Rep., 25, 1, 10.3892/mmr.2022.12581 Balatti, 2016, Novel mechanisms of regulation of miRNAs in CLL, Trends Cancer, 2, 134, 10.1016/j.trecan.2016.02.005 El-Sheikh, 2022, Insights on the potential oncogenic impact of long non-coding RNA nicotinamide nucleotide transhydrogenase antisense RNA 1 in different cancer types; integrating pathway (s) and clinical outcome (s) association, Pathol. Res. Pract., 10.1016/j.prp.2022.154183 Abd El Fattah, 2022, Interactome battling of lncRNA CCDC144NL-AS1: Its role in the emergence and ferocity of cancer and beyond, Int. J. Biol. Macromol., 10.1016/j.ijbiomac.2022.09.209 Elsakka, 2022, Megalin, a multi-ligand endocytic receptor, and its participation in renal function and diseases: a review, Life Sci., 10.1016/j.lfs.2022.120923 M. Bakr Zaki A.I. Abulsoud A.M. Elsisi A.S. Doghish O.A.E. Mansour A.I. Amin M.A. Elrebehy M.Y. Mohamed M.A. Goda Potential role of circulating microRNAs (486-5p, 497, 509-5p and 605) in metabolic syndrome Egyptian male patients Diabetes Metab. Syndr. Obes. Targets Ther. 2019 601 611. Doghish, 2021, Circulating miR-148a-5p and miR-21-5p as novel diagnostic biomarkers in Adult Egyptian male patients with metabolic syndrome, Can. J. Diabetes, 45, 614, 10.1016/j.jcjd.2020.12.005 Ismail, 2023, Beneficial and detrimental aspects of miRNAs as chief players in breast cancer: A comprehensive review, Int. J. Biol. Macromol., 224, 1541, 10.1016/j.ijbiomac.2022.10.241 Ismail, 2019, Diagnostic Significance of miR-639 and miR-10b in Βreast Cancer Patients, Meta Gene, 19, 155, 10.1016/j.mgene.2018.11.006 Elrebehy, 2022, miRNAs as cornerstones in colorectal cancer pathogenesis and resistance to therapy: a spotlight on signaling pathways interplay—A review, Int. J. Biol. Macromol., 214, 583, 10.1016/j.ijbiomac.2022.06.134 Ismail, 2022, The role of miRNAs in ovarian cancer pathogenesis and therapeutic resistance – A focus on signaling pathways interplay, Pathol. - Res. Pract., 240, 10.1016/j.prp.2022.154222 De Rie, 2017, An integrated expression atlas of miRNAs and their promoters in human and mouse, Nat. Biotechnol., 35, 872, 10.1038/nbt.3947 Newman, 2010, Emerging paradigms of regulated microRNA processing, Genes Dev., 24, 10.1101/gad.1919710 Kim, 2007, Processing of intronic microRNAs, EMBO J., 26, 10.1038/sj.emboj.7601512 Tanzer, 2004, Molecular evolution of a microRNA cluster, J. Mol. Biol., 339, 10.1016/j.jmb.2004.03.065 Mahmoud, 2021, MicroRNAs' role in the environment-related non-communicable diseases and link to multidrug resistance, regulation, or alteration, Environ. Sci. Pollut. Res Int, 28, 36984, 10.1007/s11356-021-14550-w Erturk, 2022, Mitochondrial miRNAs (MitomiRs): Their Potential Roles in Breast and Other Cancers, Mitochondrion, 10.1016/j.mito.2022.08.002 Park, 2021, Light-stabilized FHA2 suppresses miRNA biogenesis through interactions with DCL1 and HYL1, J. Mol. Plant, 14 Denli, 2004, Processing of primary microRNAs by the Microprocessor complex, Nature, 432, 10.1038/nature03049 Han, 2004, The Drosha-DGCR8 complex in primary microRNA processing, Genes Dev., 18, 3016, 10.1101/gad.1262504 Abdel Mageed, 2023, The role of miRNAs in insulin resistance and diabetic macrovascular complications – A review, Int. J. Biol. Macromol., 230, 10.1016/j.ijbiomac.2023.123189 Elkhawaga, 2023, miRNAs as cornerstones in adipogenesis and obesity, Life Sci., 315, 10.1016/j.lfs.2023.121382 Okada, 2009, A high-resolution structure of the pre-microRNA nuclear export machinery, Science, 326, 10.1126/science.1178705 Zhang, 2004, Single processing center models for human Dicer and bacterial RNase III, Cell, 118, 57, 10.1016/j.cell.2004.06.017 Zapletal, 2022, Structural and functional basis of mammalian microRNA biogenesis by Dicer, Mol. Cell, 82, 4064, 10.1016/j.molcel.2022.10.010 Wei, 2021, Structural basis of microRNA processing by Dicer-like 1, Nat. Plants, 7, 1389, 10.1038/s41477-021-01000-1 Hansen, 2016, Argonaute-associated short introns are a novel class of gene regulators, Nat. Commun., 7, 11538, 10.1038/ncomms11538 Hammond, 2015, An overview of microRNAs, Adv. Drug Deliv. Rev., 87, 3, 10.1016/j.addr.2015.05.001 Ergin, 2022, Regulation of microRNAs, miRNomics, Springer, 1 Ruby, 2007, Intronic microRNA precursors that bypass Drosha processing, Nature, 448, 83, 10.1038/nature05983 Babiarz, 2008, Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs, Genes Dev., 22, 10.1101/gad.1705308 Xie, 2013, Mammalian 5′-capped microRNA precursors that generate a single microRNA, Cell, 155, 1568, 10.1016/j.cell.2013.11.027 Yang, 2010, Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis, Proc. Natl. Acad. Sci. USA, 107, 10.1073/pnas.1006432107 Cheloufi, 2010, A dicer-independent miRNA biogenesis pathway that requires Ago catalysis, Nature, 465, 584, 10.1038/nature09092 Dragomir, 2022, Classical and noncanonical functions of miRNAs in cancers, Trends Genet, 38, 379, 10.1016/j.tig.2021.10.002 Doghish, 2022, A review of the biological role of miRNAs in prostate cancer suppression and progression, Int J. Biol. Macromol., 197, 141, 10.1016/j.ijbiomac.2021.12.141 Amit, 2020, Loss of p53 drives neuron reprogramming in head and neck cancer, Nature, 578, 449, 10.1038/s41586-020-1996-3 Franco-Zorrilla, 2007, Target mimicry provides a new mechanism for regulation of microRNA activity, Nat. Genet, 39, 10.1038/ng2079 Ebert, 2007, MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells, Nat. Methods, 4, 10.1038/nmeth1079 Yang, 2015, Hepatocellular carcinoma and microRNA: new perspectives on therapeutics and diagnostics, Adv. Drug Deliv. Rev., 81, 62, 10.1016/j.addr.2014.10.029 Fathi, 2021, Agomelatine attenuates alcohol craving and withdrawal symptoms by modulating the Notch1 signaling pathway in rats, Life Sci., 284, 10.1016/j.lfs.2021.119904 Abdelmaksoud, 2022, Genetic impact of vitamin D receptor TaqI polymorphism on the risk of osteoporotic fractures in diabetic patients, Gene Rep., 27 Elkhawaga, 2017, Clinical significance of TNFAIP3 rs2230926 T> G gene polymorphism in Egyptian cases with rheumatoid arthritis, Meta Gene, 11, 58, 10.1016/j.mgene.2016.11.005 Dragomir, 2020, Non-coding RNAs in GI cancers: from cancer hallmarks to clinical utility, Gut, 69, 748, 10.1136/gutjnl-2019-318279 Yasasve, 2022, Role of dysregulated miRNAs profiles as hallmarks in the pathogenesis and differential regulation of tongue squamous cell carcinoma, Oral. Oncol., 134, 10.1016/j.oraloncology.2022.106104 Umapathy, 2021, Transcriptional expression of miRNAs under glucose depletion/2-deoxy-d-glucose in HCC: A possible genetic footprints of angiogenesis and its hallmarks, Gene Rep., 24 Hashemi, 2022, Crosstalk of miRNAs with signaling networks in bladder cancer progression: Therapeutic, diagnostic and prognostic functions, Pharm. Res, 185, 10.1016/j.phrs.2022.106475 Hermeking, 2007, p53 enters the microRNA world, Cancer Cell, 12, 10.1016/j.ccr.2007.10.028 Volinia, 2006, A microRNA expression signature of human solid tumors defines cancer gene targets, Proc. Natl. Acad. Sci. USA, 103, 10.1073/pnas.0510565103 Al-Noshokaty, 2022, Selenium nanoparticles overcomes sorafenib resistance in thioacetamide induced hepatocellular carcinoma in rats by modulation of mTOR, NF-κB pathways and LncRNA-AF085935/GPC3 axis, J. Life Sci., 10.1016/j.lfs.2022.120675 Wu, 2020, The role of miRNA biogenesis and DDX17 in tumorigenesis and cancer stemness, Biomed. J., 43, 107, 10.1016/j.bj.2020.03.001 Ullmann, 2019, Hypoxia- and MicroRNA-Induced Metabolic Reprogramming of Tumor-Initiating Cells, Cells, 8, 528, 10.3390/cells8060528 El-Mahdy, 2020, Diltiazem potentiates the cytotoxicity of gemcitabine and 5-fluorouracil in PANC-1 human pancreatic cancer cells through inhibition of P-glycoprotein, Life Sci., 262, 10.1016/j.lfs.2020.118518 Wang, 2017, Understanding of leukemic stem cells and their clinical implications, Mol. Cancer, 16, 2, 10.1186/s12943-016-0574-7 Doghish, 2022, A study of miRNAs as cornerstone in lung cancer pathogenesis and therapeutic resistance: A focus on signaling pathways interplay, Pathol. Res. Pract., 237, 10.1016/j.prp.2022.154053 Li, 2017, MiR-155 up-regulated by TGF-β promotes epithelial-mesenchymal transition, invasion and metastasis of human hepatocellular carcinoma cells in vitro, Am. J. Transl. Res., 9, 2956 Elshimy, 2017, MiR-133a and MiR-155 as potential minimally invasive biomarkers in breast cancer, Cancer Biol., 7, 96 Elkady, 2021, MicroRNA-567 inhibits cell proliferation and induces cell apoptosis in A549 NSCLC cells by regulating cyclin-dependent kinase 8, Saudi J. Biol. Sci., 28, 2581, 10.1016/j.sjbs.2021.02.001 Sajjadi-Dokht, 2022, MicroRNAs and JAK/STAT3 signaling: A new promising therapeutic axis in blood cancers, Genes Dis., 9, 849, 10.1016/j.gendis.2021.10.009 Fulci, 2007, Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia blood, J. Am. Soc. Hematol., 109, 4944 Raveche, 2007, Abnormal microRNA-16 locus with synteny to human 13q14 linked to CLL in NZB mice, blood, J. Am. Soc. Hematol., 109, 5079 Balatti, 2015, Role of microRNA in chronic lymphocytic leukemia onset and progression, J. Hematol. Oncol., 8, 1, 10.1186/s13045-015-0112-x Veronese, 2022, Pathophysiology roles and translational opportunities of miRNAs in CLL, MicroRNA in Human Malignancies, Elsevier, 179 Zhu, 2010, miR-181b modulates multidrug resistance by targeting BCL2 in human cancer cell lines, 127, 2520 Pekarsky, 2006, Tcl1 expression in chronic lymphocytic leukemia is regulated by miR-29 and miR-181, Cancer Res., 66, 11590, 10.1158/0008-5472.CAN-06-3613 Xiao, 2008, Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes, Nat. Immunol., 9, 405, 10.1038/ni1575 Peng, 2020, Upregulation of microRNA‑1 inhibits proliferation and metastasis of breast cancer, Mol. Med. Rep., 22, 454, 10.3892/mmr.2020.11111 Frater, 2008, Dysregulated angiogenesis in B-chronic lymphocytic leukemia: morphologic, immunohistochemical, and flow cytometric evidence, Diagn. Pathol., 3, 16, 10.1186/1746-1596-3-16 Elsakka, 2020, Androgen/androgen receptor affects gentamicin-induced nephrotoxicity through regulation of megalin expression, Life Sci., 251, 10.1016/j.lfs.2020.117628 Nassar, 2022, Discovery of pyrazolo [3, 4-d] pyrimidine and pyrazolo [4, 3-e][1, 2, 4] triazolo [1, 5-c] pyrimidine derivatives as novel CDK2 inhibitors: synthesis, biological and molecular modeling investigations, RSC Adv., 12, 14865, 10.1039/D2RA01968J Kassab, 2021, Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers, J. Enzym. Inhib. Med. Chem., 36, 922, 10.1080/14756366.2021.1901089 Al-Warhi, 2022, Identification of novel cyanopyridones and pyrido [2, 3-D] pyrimidines as anticancer agents with dual VEGFR-2/HER-2 inhibitory action: synthesis, biological evaluation and molecular docking studies, Pharmaceuticals, 15, 1262, 10.3390/ph15101262 A. García-Pardo, J. Redondo-Muñoz, Regulation and function of angiogenic factors in chronic lymphocytic leukemia, (2021). Elkady, 2022, New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies, J. Enzym. Inhib. Med. Chem., 37, 403, 10.1080/14756366.2021.2015343 Hagras, 2022, 1, 3, 4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies, J. Enzym. Inhib. Med. Chem., 37, 386, 10.1080/14756366.2021.2015342 Doghish, 2021, Graphene oxide and its nanocomposites with EDTA or chitosan induce apoptosis in MCF-7 human breast cancer, RSC Adv., 11, 29052, 10.1039/D1RA04345E Wang, 2018, New insights into the regulatory role of microRNA in tumor angiogenesis and clinical implications, Mol. Cancer, 17, 22, 10.1186/s12943-018-0766-4 Ismail, 2022, Hydroxycitric acid reverses tamoxifen resistance through inhibition of ATP citrate lyase, Pathol. Res. Pract., 240, 10.1016/j.prp.2022.154211 Doghish, 2022, Nanocomposite based on gold nanoparticles and carboxymethyl cellulose: synthesis, characterization, antimicrobial, and anticancer activities, J. Drug Deliv. Sci. Technol., 77 Salem, 2022, Synthesis of silver nanocomposite based on carboxymethyl cellulose: Antibacterial, antifungal and anticancer activities, Polymers, 14, 3352, 10.3390/polym14163352 Ismail, 2020, Hydroxycitric acid potentiates the cytotoxic effect of tamoxifen in MCF-7 breast cancer cells through inhibition of ATP citrate lyase, Steroids, 160, 10.1016/j.steroids.2020.108656 Ghosh, 2009, Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells, Blood, 113, 10.1182/blood-2008-10-185686 Guinn, 2017, The regulation of tumor-suppressive microRNA, miR-126, Chronic Lymph. Leuk., 6, 778 Mraz, 2009, miR-34a, miR-29c and miR-17-5p are downregulated in CLL patients with TP53 abnormalities, Leukemia, 23, 1159, 10.1038/leu.2008.377 Vargova, 2011, MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia, Blood, 117, 3816, 10.1182/blood-2010-05-285064 Carabia, 2017, Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia, Sci. Rep., 7, 12262, 10.1038/s41598-017-12135-7 R. Visone, A. Veronese, L.Z. Rassenti, V. Balatti, D.K. Pearl, M. Acunzo, S. Volinia, C. Taccioli, T.J. Kipps, C.M. Croce, miR-181b is a biomarker of disease progression in chronic lymphocytic leukemia, Blood 118(11) (2011) 3072–3079. DOI 10.1182/blood-2011–01-333484%J Blood. Chen, 2020, MicroRNA‑425 inhibits proliferation of chronic lymphocytic leukaemia cells through regulation of the Bruton's tyrosine kinase/phospholipase Cγ2 signalling pathway, Exp. Ther. Med., 20, 1169, 10.3892/etm.2020.8771 Billard, 2014, Apoptosis inducers in chronic lymphocytic leukemia, Oncotarget, 5, 10.18632/oncotarget.1480 Cimmino, 2005, miR-15 and miR-16 induce apoptosis by targeting BCL2, Proc. Natl. Acad. Sci. USA, 102, 10.1073/pnas.0506654102 Farzadfard, 2020, Serum expression of seven MicroRNAs in chronic lymphocytic leukemia patients, J. blood Med., 11, 97, 10.2147/JBM.S230842 Ashrafi Dehkordi, 2022, Decreased cell proliferation and induced apoptosis in human B-chronic lymphocytic leukemia following miR-221 inhibition through modulation of p27 expression, Egypt. J. Med. Hum. Genet., 23, 130, 10.1186/s43042-022-00345-2 Doghish, 2019, Plasma endoglin in Type2 diabetic patients with nephropathy, Diabetes Metab. Syndr. Clin. Res. Rev., 13, 764, 10.1016/j.dsx.2018.11.058 Bottoni, 2013, MicroRNAs as main players in the pathogenesis of chronic lymphocytic leukemia, MicroRNA, 2, 158, 10.2174/2211536602666131126002337 O'Brien, 2018, Overview of MicroRNA biogenesis, mechanisms of actions, and circulation, Front Endocrinol. (Lausanne), 9, 402, 10.3389/fendo.2018.00402 Li, 2013, Role of signaling pathways and miRNAs in chronic lymphocytic leukemia, Chin. Med J., 126 Gomez-Lamarca, 2018, Activation of the notch signaling pathway in vivo elicits changes in CSL nuclear dynamics, Dev. Cell, 44, 611, 10.1016/j.devcel.2018.01.020 Palomero, 2006, NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth, Proc. Natl. Acad. Sci. USA, 103, 10.1073/pnas.0606108103 Li, 2019, miR-34a and miR-29b as indicators for prognosis of treatment-free survival of chronic lymphocytic leukemia patients in Chinese Uygur and Han populations, Mol. Cell Probes, 47, 10.1016/j.mcp.2019.101436 Wang, 2010, Cross-talk between miRNA and Notch signaling pathways in tumor development and progression, Cancer Lett., 292, 10.1016/j.canlet.2009.11.012 El-Ashmawy, 2022, Carnosine and crocin ameliorate oxidative stress in rats with rhabdomyolysis-induced acute kidney injury through upregulating HO-1 gene expression, Food, Bioscience, 49 Salman, 2014, Protective effect of proanthocyanidins on nephrotoxicity induced by antitumor dose of cisplatin in ehrlich solid tumor-bearing mice, Arab. J. Lab. Med., 40, 953 Duyu, 2014, Prospective evaluation of whole genome microRNA expression profiling in childhood acute lymphoblastic leukemia, Biomed. Res. Int., 2014, 10.1155/2014/967585 Ueno, 2013, Frizzled homolog proteins, microRNAs and Wnt signaling in cancer, Int J. Cancer, 132, 10.1002/ijc.27746 Xia, 2018, Circular RNA circ-CBFB promotes proliferation and inhibits apoptosis in chronic lymphocytic leukemia through regulating miR-607/FZD3/Wnt/beta-catenin pathway, Biochem. Biophys. Res Commun., 503, 385, 10.1016/j.bbrc.2018.06.045 Smith, 2021, Non-coding RNA and frizzled receptors in cancer, Front Mol. Biosci., 8, 10.3389/fmolb.2021.712546 Choudhry, 2014, Sonic hedgehog signalling pathway: a complex network, Ann. Neurosci., 21, 28, 10.5214/ans.0972.7531.210109 Sari, 2018, Hedgehog signaling in cancer: a prospective therapeutic target for eradicating cancer stem cells, Cells, 7, 10.3390/cells7110208 Ok, 2012, Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms, Am. J. Pathol., 180, 2, 10.1016/j.ajpath.2011.09.009 Sheybani, 2019, The Hedgehog signal transducer Smoothened and microRNA-326: pathogenesis and regulation of drug resistance in pediatric B-cell acute lymphoblastic leukemia, Cancer Manag. Res., 11, 7621, 10.2147/CMAR.S214405 Ma, 2014, miR-212 promotes pancreatic cancer cell growth and invasion by targeting the hedgehog signaling pathway receptor patched-1, J. Exp. Clin. Cancer Res, 33, 54, 10.1186/1756-9966-33-54 Han, 2022, The emerging role of noncoding RNAs in the Hedgehog signaling pathway in cancer, Biomed. Pharmacother. Biomed. Pharmacother., 154 Harrison, 2012, The Jak/STAT pathway, Cold Spring Harb. Perspect. Biol., 4, 10.1101/cshperspect.a011205 Vainchenker, 2013, JAK/STAT signaling in hematological malignancies, Oncogene, 32, 10.1038/onc.2012.347 Tosic, 2021, STAT3 as a mediator of oncogenic cellular metabolism: Pathogenic and therapeutic implications, Neoplasia, 23, 1167, 10.1016/j.neo.2021.10.003 Rawat, 2019, MicroRNA in pancreatic cancer: from biology to therapeutic potential, Genes, 10, 10.3390/genes10100752 Zanette, 2007, miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia, Braz. J. Med Biol. Res, 40, 10.1590/S0100-879X2007001100003 Szymczyk, 2018, Abnormal microRNA expression in the course of hematological malignancies, Cancer Manag. Res., 10, 4267, 10.2147/CMAR.S174476 Carabia, 2017, Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia, Sci. Rep., 7, 12262, 10.1038/s41598-017-12135-7 Chen, 2018, Overexpression of IL-9 induced by STAT3 phosphorylation is mediated by miR-155 and miR-21 in chronic lymphocytic leukemia, Oncol. Rep., 39, 3064 Zanoaga, 2021, The role of miR-155 in nutrition: modulating cancer-associated inflammation, Nutrients, 13, 10.3390/nu13072245 Ye, 2016, miR-155 regulated inflammation response by the SOCS1-STAT3-PDCD4 axis in Atherogenesis, Mediat. Inflamm., 2016, 8060182, 10.1155/2016/8060182 Hanlon, 2009, Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL, PLoS One, 4, 10.1371/journal.pone.0007169 Veronese, 2015, Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia, Leukemia, 29, 86, 10.1038/leu.2014.139 ten Hacken, 2019, The importance of B cell receptor isotypes and stereotypes in chronic lymphocytic leukemia, Leukemia, 33, 287, 10.1038/s41375-018-0303-x Xiao, 2007, MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb, Cell, 131, 10.1016/j.cell.2007.07.021 Okuyama, 2013, MicroRNA-126-mediated control of cell fate in B-cell myeloid progenitors as a potential alternative to transcriptional factors, Proc. Natl. Acad. Sci. USA, 110, 10.1073/pnas.1220710110 Chen, 2004, MicroRNAs modulate hematopoietic lineage differentiation, Science, 303, 10.1126/science.1091903 Kurkewich, 2016, The mirn23a microRNA cluster antagonizes B cell development, J. Leukoc. Biol., 100, 665, 10.1189/jlb.1HI0915-398RR Nechanitzky, 2013, Transcription factor EBF1 is essential for the maintenance of B cell identity and prevention of alternative fates in committed cells, Nat. Immunol., 14, 867, 10.1038/ni.2641 Blume, 2019, miR-191 modulates B-cell development and targets transcription factors E2A, Foxp1, and Egr1, Eur. J. Immunol., 49, 121, 10.1002/eji.201847660 Contreras, 2015, MicroRNA-146a modulates B-cell oncogenesis by regulating Egr1, Oncotarget, 6, 11023, 10.18632/oncotarget.3433 Cui, 2014, MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia blood, J. Am. Soc. Hematol., 124, 546 Mraz, 2014, miR-150 influences B-cell receptor signaling in chronic lymphocytic leukemia by regulating expression of GAB1 and FOXP1, Blood, J. Am. Soc. Hematol., 124, 84 Cerna, 2019, MicroRNA miR-34a downregulates FOXP1 during DNA damage response to limit BCR signalling in chronic lymphocytic leukaemia B cells, Leukemia, 33, 403, 10.1038/s41375-018-0230-x Sharma, 2021, miR-29 modulates CD40 signaling in chronic lymphocytic leukemia by targeting TRAF4: an axis affected by BCR inhibitors, Blood, 137, 2481, 10.1182/blood.2020005627 Shukla, 2016, Sprouty 2: a novel attenuator of B-cell receptor and MAPK-Erk signaling in CLL, blood, J. Am. Soc. Hematol., 127, 2310 Kawai, 2007, TLR signaling, Semin Immunol., 19, 24, 10.1016/j.smim.2006.12.004 Kawai, 2011, Toll-like receptors and their crosstalk with other innate receptors in infection and immunity, Immunity, 34, 10.1016/j.immuni.2011.05.006 Balkwill, 2004, An inflammatory link, Nature, 431, 405, 10.1038/431405a Bomben, 2012, The miR-17∼ 92 family regulates the response to Toll-like receptor 9 triggering of CLL cells with unmutated IGHV genes, Leukemia, 26, 1584, 10.1038/leu.2012.44 Fabbri, 2012, MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response, Proc. Natl. Acad. Sci. USA, 109, 10.1073/pnas.1209414109 Curtale, 2013, Negative regulation of Toll-like receptor 4 signaling by IL-10–dependent microRNA-146b, Proc. Natl. Acad. Sci., 110, 11499, 10.1073/pnas.1219852110 Ntoufa, 2016, B cell anergy modulated by TLR1/2 and the miR-17∼ 92 cluster underlies the indolent clinical course of chronic lymphocytic leukemia stereotyped subset# 4, J. Immunol., 196, 4410, 10.4049/jimmunol.1502297 Zhuang, 2010, Akt is activated in chronic lymphocytic leukemia cells and delivers a pro-survival signal: the therapeutic potential of Akt inhibition, haematologica, 95, 110, 10.3324/haematol.2009.010272 Xu, 2012, The AKT-associated microRNAs, Cell. Mol. life Sci., 69, 3601, 10.1007/s00018-012-1129-8 Carl Philipp, 2018, Microenvironmental stromal cells abrogate NF-κB inhibitor-induced apoptosis in chronic lymphocytic leukemia, Haematologica, 103, 136, 10.3324/haematol.2017.165381 Baer, 2015, Epigenetic silencing of miR‐708 enhances NF‐κB signaling in chronic lymphocytic leukemia, Int. J. Cancer, 137, 1352, 10.1002/ijc.29491 Fabris, 2020, Non-coding RNAs as cancer hallmarks in chronic lymphocytic leukemia, Int. J. Mol. Sci., 21, 10.3390/ijms21186720 Blume, 2015, p53-dependent non-coding RNA networks in chronic lymphocytic leukemia, Leukemia, 29, 2015, 10.1038/leu.2015.119 Jurj, 2018, Exosome-carried microRNA-based signature as a cellular trigger for the evolution of chronic lymphocytic leukemia into Richter syndrome, Crit. Rev. Clin. Lab. Sci., 55, 501, 10.1080/10408363.2018.1499707 Tavolaro, 2015, Increased chronic lymphocytic leukemia proliferation upon IgM stimulation is sustained by the upregulation of miR‐132 and miR‐212, Genes Chromosomes Cancer, 54, 222, 10.1002/gcc.22236 Ferracin, 2010, MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia, Mol. Cancer, 9, 1, 10.1186/1476-4598-9-123 Curtale, 2013, Negative regulation of Toll-like receptor 4 signaling by IL-10–dependent microRNA-146b, 110, 11499 Giacopelli, 2016, Comparative evaluation of prognostic factors that assess the natural history of chronic lymphocytic leukemia, Blood, 128, 968, 10.1182/blood.V128.22.968.968 Mirzaei, 2018, State of the art in microRNA as diagnostic and therapeutic biomarkers in chronic lymphocytic leukemia, J. Cell. Physiol., 233, 888, 10.1002/jcp.25799 Fathullahzadeh, 2016, Circulating microRNA-192 as a diagnostic biomarker in human chronic lymphocytic leukemia, Cancer Gene Ther., 23, 327, 10.1038/cgt.2016.34 Li, 2011, MicroRNA expression profiling identifies activated B cell status in chronic lymphocytic leukemia cells, PloS One, 6, 10.1371/journal.pone.0016956 Cang, 2015, ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development, J. Hematol. Oncol., 8, 129, 10.1186/s13045-015-0224-3 Ashofteh, 2022, MiRNA-16-1 suppresses Mcl-1 and Bcl-2 and sensitizes chronic lymphocytic leukemia cells to BH3 Mimetic ABT-199, Cell J., 24 Zhu, 2012, miR-181a/b significantly enhances drug sensitivity in chronic lymphocytic leukemia cells via targeting multiple anti-apoptosis genes, Carcinogenesis, 33, 1294, 10.1093/carcin/bgs179 Szymczyk, 2019, Assessment of microRNA expression in leukemic cells as predictors of sensitivity to purine nucleoside analogs, fludarabine and cladribine, in chronic lymphocytic leukemia patients, Cancer Manag. Res., 11, 5021, 10.2147/CMAR.S191311 Liu, 2014, Loss of p53 and altered miR15-a/16-1→MCL-1 pathway in CLL: insights from TCL1-Tg:p53−/− mouse model and primary human leukemia cells, Leukemia, 28, 118, 10.1038/leu.2013.125 Salerno, 2009, Correcting miR-15a/16 genetic defect in New Zealand Black mouse model of CLL enhances drug sensitivity, Mol. Cancer Ther., 8, 2684, 10.1158/1535-7163.MCT-09-0127 Ferracin, 2010, MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia, Mol. Cancer, 9, 123, 10.1186/1476-4598-9-123 Fonte, 2013, In vitro sensitivity of CLL cells to fludarabine may be modulated by the stimulation of toll-like receptors, Clin. Cancer Res., 19, 367, 10.1158/1078-0432.CCR-12-1922 Kapoor, 2021, Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies, Cell Death Dis., 12, 1061, 10.1038/s41419-021-04353-9 Cao, 2020, Downregulation of microRNA let-7f mediated the Adriamycin resistance in leukemia cell line, J. Cell. Biochem., 121, 4022, 10.1002/jcb.29541 Anne-Laure, 2017, miR-125b and miR-532-3p predict the efficiency of rituximab-mediated lymphodepletion in chronic lymphocytic leukemia patients. A French Innovative Leukemia Organization study, Haematologica, 102, 746, 10.3324/haematol.2016.153189 Grasedieck, 2012, Impact of serum storage conditions on microRNA stability, Leukemia, 26, 2414, 10.1038/leu.2012.106 Makarova, 2016, Intracellular and extracellular microRNA: an update on localization and biological role, Prog. Histochem. Cytochem., 51, 33, 10.1016/j.proghi.2016.06.001 Li, 2019, MicroRNAs: key players in bladder cancer, Mol. Diagn. Ther., 23, 579, 10.1007/s40291-019-00410-4 G.A. Calin, C.M. Croce, Genomics of chronic lymphocytic leukemia microRNAs as new players with clinical significance, Elsevier, pp. 167–173.