Exosome-carried microRNA-based signature as a cellular trigger for the evolution of chronic lymphocytic leukemia into Richter syndrome

References

• Anderson MA, Blombery P, Seymour JF. Transformed Lymphoma. Hematology/oncology Clin North America. 2016;30:1317–1332.
   PubMed Web of Science ®Google Scholar
• Soma LA, Craig FE, Swerdlow SH. The proliferation center microenvironment and prognostic markers in chronic lymphocytic leukemia/small lymphocytic lymphoma. Hum Pathol. 2006;37:152–159.
   PubMed Web of Science ®Google Scholar
• Bertilaccio MT, Scielzo C, Muzio M, et al. An overview of chronic lymphocytic leukaemia biology. Best Prac Res Clin Haematol. 2010;23:21–32.
   PubMed Web of Science ®Google Scholar
• Zenz T, Mertens D, Kuppers R, et al. From pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev Cancer. 2010;10:37–50.
   PubMed Web of Science ®Google Scholar
• Bonato M, Pittaluga S, Tierens A, et al. Lymph node histology in typical and atypical chronic lymphocytic leukemia. Amer J Surg Pathol. 1998;22:49–56.
   PubMed Web of Science ®Google Scholar
• Gine E, Martinez A, Villamor N, et al. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica. 2010;95:1526–1533.
   PubMed Web of Science ®Google Scholar
• Lennert KMN, Stein H. Malignant lymphomas and Hodgkin’s disease. In: Cavalli GB, Marcel Rozencweig, editor. Experimental and Therapeutic Advances Franco. Berlin·Heidelberg·New York: Springler-Verlag; 1978. p. 167–186.
   Google Scholar
• Richter MN. Generalized Reticular Cell Sarcoma of Lymph Nodes Associated with Lymphatic Leukemia. Am J Pathol. 1928;4:285–292.
   PubMedGoogle Scholar
• Lortholary P, Boiron M, Ripault P, et al. [Chronic Lymphoid Leukemia Secondarily Associated with a Malignant Reticulopathy: Richter's Syndrome. Nouv Rev Fr Hematol. 1964;4:621–644.
   PubMedGoogle Scholar
• Jamroziak K, Grzybowska-Izydorczyk O, Jesionek-Kupnicka D, et al. Poor prognosis of Hodgkin variant of Richter transformation in chronic lymphocytic leukemia treated with cladribine. Br J Haematol. 2012;158:286–288.
   PubMed Web of Science ®Google Scholar
• Grewal R, Irimie A, Naidoo N, et al. Hodgkin's lymphoma and its association with EBV and HIV infection. Critic Rev Clin Lab Sci. 2018;55:102–114.
   PubMed Web of Science ®Google Scholar
• Jaffe ES, Pittaluga S. Aggressive B-cell lymphomas: a review of new and old entities in the WHO classification. Hematolo Amer Soc Hematol Educ Prog. 2011;2011:506–514.
   PubMedGoogle Scholar
• Aboulafia DM, Lee RM, Hafermann M, et al. Extramedullary facial plasmacytomas with anaplastic features: a diagnostic dilemma with implications for treatment. Amer J Clin Oncolo. 1998;21:401–405.
   PubMed Web of Science ®Google Scholar
• Nakamura N, Kuze T, Hashimoto Y, et al. Richter transformation of a T cell phenotype with p53 gene mutation. Eur J Haematol. 1997;59:331–332.
   PubMed Web of Science ®Google Scholar
• Sun T, Grupka N, Klein C. Transformation of hairy cell leukemia to high-grade lymphoma: a case report and review of the literature. Hum Pathol. 2004;35:1423–1426.
   PubMed Web of Science ®Google Scholar
• Reiniger L, Bodor C, Bognar A, et al. Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation. Leukemia. 2006;20:1089–1095.
   PubMed Web of Science ®Google Scholar
• Jain N, Keating MJ. Richter transformation of CLL. Expert Rev Hematol. 2016;9:793–801.
   PubMed Web of Science ®Google Scholar
• Harousseau JL, Flandrin G, Tricot G, et al. Malignant lymphoma supervening in chronic lymphocytic leukemia and related disorders. Richter's syndrome: a study of 25 cases. Cancer. 1981;48:1302–1308.
   PubMed Web of Science ®Google Scholar
• McDonnell JM, Beschorner WE, Staal SP, et al. Richter's syndrome with two different B-cell clones. Cancer. 1986;58:2031–2037.
   PubMed Web of Science ®Google Scholar
• Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Amer J Surg Pathol. 2007;31:1605–1614.
   PubMed Web of Science ®Google Scholar
• Bagacean C, Tempescul A, Le Dantec C, et al. Alterations in DNA methylation/demethylation intermediates predict clinical outcome in chronic lymphocytic leukemia. Oncotarget. 2017;8:65699–65716.
   PubMedGoogle Scholar
• Rossi D, Spina V, Forconi F, et al. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis. Int J Cancer. 2012;130:3006–3010.
   PubMed Web of Science ®Google Scholar
• Chigrinova E, Rinaldi A, Kwee I, et al. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood. 2013;122:2673–2682.
   PubMed Web of Science ®Google Scholar
• Ciccone M, Ferrajoli A, Keating MJ, et al. SnapShot: chronic lymphocytic leukemia. Cancer Cell. 2014;26:770–7e1.
   PubMed Web of Science ®Google Scholar
• Negrini M, Cutrona G, Bassi C, et al. microRNAome expression in chronic lymphocytic leukemia: comparison with normal B-cell subsets and correlations with prognostic and clinical parameters. Clin Cancer Res. 2014;20:4141–4153.
   PubMed Web of Science ®Google Scholar
• Braicu C, Tomuleasa C, Monroig P, et al. Exosomes as divine messengers: are they the Hermes of modern molecular oncology? Cell Death Differ. 2015;22:34–45.
   PubMed Web of Science ®Google Scholar
• Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111:5446–5456.
   PubMed Web of Science ®Google Scholar
• Bagacean C, Zdrenghea M, Dantec CL, et al. DNA demethylation marks in chronic lymphocytic leukemia: it is time to let the cat out of the bag. Future Science OA. 2018;4:FSO265.
   PubMed Web of Science ®Google Scholar
• Rinaldi A, Mensah AA, Kwee I, et al. Promoter methylation patterns in Richter syndrome affect stem-cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma. Brit J Haematol. 2013;163:194–204.
   PubMed Web of Science ®Google Scholar
• Bernards R, Weinberg RA. A progression puzzle. Nature. 2002;418:823.
   PubMed Web of Science ®Google Scholar
• Brabletz T, Kalluri R, Nieto MA, et al. EMT in cancer. Nat Rev Cancer. 2018;18:128–134.
   PubMed Web of Science ®Google Scholar
• Pattabiraman DR, Weinberg RA. Targeting the Epithelial-to-Mesenchymal Transition: The Case for Differentiation-Based Therapy. Cold Spring Harb Symp Quant Biol. 2016;81:11–19.
   PubMedGoogle Scholar
• Cahill DP, Lengauer C, Yu J, et al. Mutations of mitotic checkpoint genes in human cancers. Nature. 1998;392:300–303.
   PubMed Web of Science ®Google Scholar
• Tomuleasa C, Zaharie F, Muresan MS, et al. How to Diagnose and Treat a Cancer of Unknown Primary Site. J Gastrointestin Liver Dis. 2017;26:69–79.
   PubMed Web of Science ®Google Scholar
• Zaharie F, Muresan MS, Petrushev B, et al. Exosome-Carried microRNA-375 Inhibits Cell Progression and Dissemination via Bcl-2 Blocking in Colon Cancer. J Gastrointestin Liver Dis. 2015;24:435–443.
   PubMed Web of Science ®Google Scholar
• Tomuleasa C, Soritau O, Rus-Ciuca D, et al. Isolation and characterization of hepatic cancer cells with stem-like properties from hepatocellular carcinoma. JGLD. 2010;19:61–67.
   PubMed Web of Science ®Google Scholar
• Qian L, Dima D, Berce C, et al. Protein dysregulation in graft versus host disease. Oncotarget. 2018;9:1483–1491.
   PubMedGoogle Scholar
• Li L, Masica D, Ishida M, et al. Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology. 2014;60:896–907.
   PubMed Web of Science ®Google Scholar
• Panagiotara A, Markou A, Lianidou ES, et al. Exosomes: A Cancer Theranostics Road Map. Public Health Genomics. 2017;20:116–125.
   PubMed Web of Science ®Google Scholar
• Dolatmoradi A, Mirtaheri E, El-Zahab B. Thermo-acoustofluidic separation of vesicles based on cholesterol content. Lab Chip. 2017;17:1332–1339.
   PubMed Web of Science ®Google Scholar
• Caponnetto F, Manini I, Skrap M, et al. Size-dependent cellular uptake of exosomes. Nanomed Nanotechnol Biol Med. 2017;13:1011–1020.
   PubMed Web of Science ®Google Scholar
• Kooijmans SAA, Schiffelers RM, Zarovni N, et al. Modulation of tissue tropism and biological activity of exosomes and other extracellular vesicles: New nanotools for cancer treatment. Pharmacol Res. 2016;111:487–500.
   PubMed Web of Science ®Google Scholar
• Chi KR. The tumour trail left in blood. Nature. 2016;532:269–271.
   PubMed Web of Science ®Google Scholar
• Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164:1226–1232.
   PubMed Web of Science ®Google Scholar
• Liu Y, Cao X. Organotropic metastasis: role of tumor exosomes. Cell Res. 2016;26:149–150.
   PubMed Web of Science ®Google Scholar
• Rak J. Cancer: Organ-seeking vesicles. Nature. 2015;527:312–314.
   PubMed Web of Science ®Google Scholar
• Hoshino A, Costa-Silva B, Shen TL, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–335.
   PubMed Web of Science ®Google Scholar
• Wang F, Li L, Piontek K, et al. Exosome miR-335 as a novel therapeutic strategy in hepatocellular carcinoma. Hepatology. 2018;67:940–954.
   PubMed Web of Science ®Google Scholar
• Li L, Piontek K, Ishida M, et al. Extracellular vesicles carry microRNA-195 to intrahepatic cholangiocarcinoma and improve survival in a rat model. Hepatology. 2017;65:501–514.
   PubMed Web of Science ®Google Scholar
• Gulei D, Irimie AI, Cojocneanu-Petric R, et al. Exosomes-small players, big sound. Bioconjug Chem. 2018;29:635–648.
   PubMed Web of Science ®Google Scholar
• Thery C. Cancer: Diagnosis by extracellular vesicles. Nature. 2015;523:161–162.
   PubMed Web of Science ®Google Scholar
• Keerthikumar S, Gangoda L, Liem M, et al. Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes. Oncotarget. 2015;6:15375–15396.
   PubMed Web of Science ®Google Scholar
• Andersson R, Gebhard C, Miguel-Escalada I, et al. An atlas of active enhancers across human cell types and tissues. Nature. 2014;507:455–461.
   PubMed Web of Science ®Google Scholar
• Mondal A, Kumari Singh D, Panda S, et al. Extracellular Vesicles As Modulators of Tumor Microenvironment and Disease Progression in Glioma. Front Oncol. 2017;7:144.
   PubMed Web of Science ®Google Scholar
• Mateescu B, Kowal EJ, van Balkom BW, et al. Obstacles and opportunities in the functional analysis of extracellular vesicle RNA - an ISEV position paper. J Extracell Ves. 2017;6:1286095.
   PubMed Web of Science ®Google Scholar
• Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: masters of intercellular communication and potential clinical interventions. J Clin Invest. 2016;126:1139–1143.
   PubMed Web of Science ®Google Scholar
• Lee HM, Choi EJ, Kim JH, et al. A membranous form of ICAM-1 on exosomes efficiently blocks leukocyte adhesion to activated endothelial cells. Biochem Biophys Res Commun. 2010;397:251–256.
   PubMed Web of Science ®Google Scholar
• Chairoungdua A, Smith DL, Pochard P, et al . Exosome release of β-catenin: a novel mechanism that antagonizes Wnt signaling. J Cell Biol. 2010;190:1079–1091.
   PubMed Web of Science ®Google Scholar
• Bortoluzzi S, Lovisa F, Gaffo E, et al. Small RNAs in Circulating Exosomes of Cancer Patients: A Minireview. High-throughput. 2017;6:13.
   Google Scholar
• Cooks T, Pateras IS, Jenkins LM, et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun. 2018;9:771.
   PubMed Web of Science ®Google Scholar
• Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015;523:177–182.
   PubMed Web of Science ®Google Scholar
• Weber C. Biomarkers: The challenge to find biomarkers for the early detection of pancreatic cancer. Nat Rev Gastroenterol Hepatol. 2015;12:427.
   PubMedGoogle Scholar
• Alderton GK. Diagnosis: Fishing for exosomes. Nat Rev Cancer. 2015;15:453.
   PubMed Web of Science ®Google Scholar
• Whiteside TL, Boyiadzis M. Response commentary: exosomes vs microvesicles in hematological malignancies. Leukemia. 2017;31:2277.
   PubMed Web of Science ®Google Scholar
• Hong CS, Sharma P, Yerneni SS, et al. Circulating exosomes carrying an immunosuppressive cargo interfere with cellular immunotherapy in acute myeloid leukemia. Sci Rep. 2017;7:14684.
   PubMed Web of Science ®Google Scholar
• Bayraktar R, Van Roosbroeck K, Calin GA. Cell-to-cell communication: microRNAs as hormones. Mol Oncol. 2017;11:1673–1686.
   PubMed Web of Science ®Google Scholar
• Gitter R, Alivizators P, Capehart J, et al. Aprotinin and aortic cannula thrombosis. J Thorac Cardiovasc Surg. 1996;112:537–538.
   PubMed Web of Science ®Google Scholar
• Caivano A, Del Vecchio L, Musto P. Do we need to distinguish exosomes from microvesicles in hematological malignancies? Leukemia. 2017;31:2009–2010.
   PubMed Web of Science ®Google Scholar
• Boyiadzis M, Whiteside TL. The emerging roles of tumor-derived exosomes in hematological malignancies. Leukemia. 2017;31:1259–1268.
   PubMed Web of Science ®Google Scholar
• Li P, Feng J, Liu Y, et al. Novel therapy for glioblastoma multiforme by restoring lrrc4 in tumor cells: lrrc4 inhibits tumor-infitrating regulatory t cells by cytokine and programmed cell death 1-containing exosomes. Front Immunol. 2017;8:1748.
   PubMed Web of Science ®Google Scholar
• Whiteside TL. Exosome and mesenchymal stem cell cross-talk in the tumor microenvironment. Semin Immunol. 2018;35:69–79.
   PubMed Web of Science ®Google Scholar
• Nogues L, Benito-Martin A, Hergueta-Redondo M, et al. The influence of tumour-derived extracellular vesicles on local and distal metastatic dissemination. Mol Aspects Med. 2018;60:15–26.
   PubMed Web of Science ®Google Scholar
• Peinado H, Alec kovic M, Lavotshkin S, et al. Corrigendum: Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2016;22:1502.
   PubMed Web of Science ®Google Scholar
• Garcia-Silva S, Peinado H. Melanosomes foster a tumour niche by activating CAFs. Nat Cell Biol. 2016;18:911–913.
   PubMed Web of Science ®Google Scholar
• Ratajczak MZ, Ratajczak J. Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later. Clin Trans Med. 2016;5:7.
   PubMed Web of Science ®Google Scholar
• Ratajczak MZ, Ratajczak J. Extracellular microvesicles as game changers in better understanding the complexity of cellular interactions-from bench to clinical applications. Am J Med Sci. 2017;354:449–452.
   PubMed Web of Science ®Google Scholar
• Janowska-Wieczorek A, Wysoczynski M, Kijowski J, et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer. 2005;113:752–760.
   PubMed Web of Science ®Google Scholar
• van Attekum MH, Eldering E, Kater AP. Chronic lymphocytic leukemia cells are active participants in microenvironmental cross-talk. Haematologica. 2017;102:1469–1476.
   PubMedGoogle Scholar
• Prieto D, Sotelo N, Seija N, et al. S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-kappaB activity during disease progression. Blood. 2017;130:777–788.
   PubMed Web of Science ®Google Scholar
• Mirzaei H, Fathullahzadeh S, Khanmohammadi R, et al. State of the art in microRNA as diagnostic and therapeutic biomarkers in chronic lymphocytic leukemia. J Cell Physiol. 2018;233:888–900.
   PubMed Web of Science ®Google Scholar
• Kostakoglu L. Noninvasive detection of multidrug resistance in patients with hematological malignancies: are we there yet?. Clin Lymphoma. 2002;2:242–248.
   PubMedGoogle Scholar
• Apollonio B, Ramsay AG. Exosomes and CAFs: partners in crime. Blood. 2015;126:1053–1055.
   PubMed Web of Science ®Google Scholar
• Yeh YY, Ozer HG, Lehman AM, et al. Characterization of CLL exosomes reveals a distinct microRNA signature and enhanced secretion by activation of BCR signaling. Blood. 2015;125:3297–3305.
   PubMed Web of Science ®Google Scholar
• Paggetti J, Haderk F, Seiffert M, et al. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts. Blood. 2015;126:1106–1117.
   PubMed Web of Science ®Google Scholar
• Guan XW, Zhao F, Wang JY, et al. Tumor microenvironment interruption: a novel anti-cancer mechanism of Proton-pump inhibitor in gastric cancer by suppressing the release of microRNA-carrying exosomes. Amer J Cancer Res. 2017;7:1913–1925.
   PubMed Web of Science ®Google Scholar
• Parolini I, Federici C, Raggi C, et al. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem. 2009;284:34211–34222.
   PubMed Web of Science ®Google Scholar
• Jurj A, Braicu C, Pop LA, et al. The new era of nanotechnology, an alternative to change cancer treatment. Drug Des Devel Ther. 2017;11:2871–2890.
   PubMed Web of Science ®Google Scholar
• Grewal R, Cucuianu A, Swanepoel C, et al. The role of microRNAs in the pathogenesis of HIV-related lymphomas. Crit Rev Clin Lab Sci. 2015;52:232–241.
   PubMed Web of Science ®Google Scholar
• Tomuleasa C, Fuji S, Cucuianu A, et al. MicroRNAs as biomarkers for graft-versus-host disease following allogeneic stem cell transplantation. Ann Hematol. 2015;94:1081–1092.
   PubMed Web of Science ®Google Scholar
• Muresan M, Zaharie F, Bojan A, et al. MicroRNAs in liver malignancies. Basic science applied in surgery. BUON. 2015;20:361–375.
   PubMed Web of Science ®Google Scholar
• Li L, Zhou L, Li Y, et al. MicroRNA-21 stimulates gastric cancer growth and invasion by inhibiting the tumor suppressor effects of programmed cell death protein 4 and phosphatase and tensin homolog. BUON. 2014;19:228–236.
   PubMed Web of Science ®Google Scholar
• Susman S, Tomuleasa C, Fekete Z, et al. The importance of microRNAs in the stroma-breast cancer cell interplay. CBM. 2014;14:137–144.
   PubMedGoogle Scholar
• Yamanaka S, Olaru AV, An F, et al. MicroRNA-21 inhibits Serpini1, a gene with novel tumour suppressive effects in gastric cancer. Digestive and Liver Disease: official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2012;44:589–596.
   PubMedGoogle Scholar
• Samoil V, Dagenais M, Ganapathy V, et al. Vesicle-based secretion in schistosomes: Analysis of protein and microRNA (miRNA) content of exosome-like vesicles derived from Schistosoma mansoni. Sci Rep. 2018;8:3286.
   PubMed Web of Science ®Google Scholar
• Tran N. Cancer Exosomes as miRNA Factories. Trends Cancer. 2016;2:329–331.
   PubMed Web of Science ®Google Scholar
• Zhang L, Zhang S, Yao J, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527:100–104.
   PubMed Web of Science ®Google Scholar
• Bagacean C, Le Dantec C, Berthou C, et al. Combining cytogenetic and epigenetic approaches in chronic lymphocytic leukemia improves prognosis prediction for patients with isolated 13q deletion. Clin Epigenet. 2017;9:122.
   PubMed Web of Science ®Google Scholar
• Fabbri G, Khiabanian H, Holmes AB, et al. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med. 2013;210:2273–2288.
   PubMed Web of Science ®Google Scholar
• Boca S, Berce C, Jurj A, et al. Ruxolitinib-conjugated gold nanoparticles for topical administration: An alternative for treating alopecia? Medical Hypotheses. 2017;109:42–45.
   PubMed Web of Science ®Google Scholar
• Tomuleasa C, Soritau O, Orza A, et al. Gold nanoparticles conjugated with cisplatin/doxorubicin/capecitabine lower the chemoresistance of hepatocellular carcinoma-derived cancer cells. JGLD. 2012;21:187–196.
   PubMed Web of Science ®Google Scholar
• Petrushev B, Boca S, Simon T, et al. Gold nanoparticles enhance the effect of tyrosine kinase inhibitors in acute myeloid leukemia therapy. Int J Nanomed. 2016;11:641–660.
   PubMed Web of Science ®Google Scholar
• Aldea MD, Petrushev B, Soritau O, et al. Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells. BUON. 2014;19:502–511.
   PubMed Web of Science ®Google Scholar
• Petrushev B, Tomuleasa C, Soritau O, et al. Metformin plus PIAF combination chemotherapy for hepatocellular carcinoma. Exp Oncol. 2011;4:60–24.
   Google Scholar
• Soritau O, Tomuleasa C, Aldea M, et al. Metformin plus temozolomide-based chemotherapy as adjuvant treatment for WHO grade III and IV malignant gliomas. BUON. 2011;16:282–289.
   PubMedGoogle Scholar
• Tomuleasa C, Soritau O, Brie I, et al. Mesenchymal stem cell irradiation in culture engages differential effect of hyper-fractionated radiotherapy for head and neck cancers. BUON. 2010;15:348–356.
   PubMed Web of Science ®Google Scholar
• Soriţău O, Tomuleasa CI, Páll E, et al. Enhanced chemoresistance and tumor sphere formation as a laboratory model for peritoneal micrometastasis in epithelial ovarian cancer. Rom J Morphol Embryol. 2010;51:259–264.
   PubMed Web of Science ®Google Scholar
• Pall E, Groza I, Cenariu M, et al. Establishment of an embryonic stem cell line from blastocyst stage mouse embryos.  Rom J Morphol Embryol. 2011;52:1005–1010.
   Google Scholar
• Fischer-Fodor E, Miklas R, Risianova L, et al. Novel Palladium(II) Complexes that Influence Prominin-1/CD133 Expression and Stem Cell Factor Release in Tumor Cells. Molecules. 2017;22:561.
   Web of Science ®Google Scholar
• Miklasova N, Fischer-Fodor E, Lonnecke P, et al. Antiproliferative effect of novel platinum(II) and palladium(II) complexes on hepatic tumor stem cells in vitro. Europe J Med Chem. 2012;49:41–47.
   PubMed Web of Science ®Google Scholar
• Tatar AS, Nagy-Simon T, Tomuleasa C, et al. Nanomedicine approaches in acute lymphoblastic leukemia. J Control Release. 2016;238:123–138.
   PubMed Web of Science ®Google Scholar
• Boyiadzis M, Whiteside TL. Plasma-derived exosomes in acute myeloid leukemia for detection of minimal residual disease: are we ready? Exp Rev Mol Diag. 2016;16:623–629.
   PubMed Web of Science ®Google Scholar
• Fabbri M, Bottoni A, Shimizu M, et al. Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. Jama. 2011;305:59–67.
   PubMed Web of Science ®Google Scholar
• Calin GA, Ferracin M, Cimmino A, et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med. 2005;353:1793–1801.
   PubMed Web of Science ®Google Scholar
• Peng H, Ishida M, Li L, et al. Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma. Oncotarget. 2015;6:5666–5677.
   PubMedGoogle Scholar
• Schroers R, Griesinger F, Trumper L, et al. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Leukemia. 2005;19:750–758.
   PubMed Web of Science ®Google Scholar
• Bea S, Lopez-Guillermo A, Ribas M, et al. Genetic imbalances in progressed B-cell chronic lymphocytic leukemia and transformed large-cell lymphoma (Richter's syndrome). The American Journal of Pathology. 2002;161:957–968.
   PubMed Web of Science ®Google Scholar
• Dighiero G, Hamblin TJ. Chronic lymphocytic leukaemia. Lancet. 2008;371:1017–1029.
   PubMed Web of Science ®Google Scholar
• Zenz T, Krober A, Scherer K, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008;112:3322–3329.
   PubMed Web of Science ®Google Scholar
• Dicker F, Herholz H, Schnittger S, et al. The detection of TP53 mutations in chronic lymphocytic leukemia independently predicts rapid disease progression and is highly correlated with a complex aberrant karyotype. Leukemia. 2009;23:117–124.
   PubMed Web of Science ®Google Scholar
• Shanafelt TD, Witzig TE, Fink SR, et al. Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. Jco. 2006;24:4634–4641.
   PubMed Web of Science ®Google Scholar
• Pospisilova S, Gonzalez D, Malcikova J, et al. ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia. 2012;26:1458–1461.
   PubMed Web of Science ®Google Scholar
• Gonzalez D, Martinez P, Wade R, et al. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. Jco. 2011;29:2223–2229.
   PubMed Web of Science ®Google Scholar
• Cobo F, Martinez A, Pinyol M, et al. Multiple cell cycle regulator alterations in Richter's transformation of chronic lymphocytic leukemia. Leukemia. 2002;16:1028–1034.
   PubMed Web of Science ®Google Scholar
• Travis LB, Curtis RE, Hankey BF, et al. Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst. 1992;84:1422–1427.
   PubMed Web of Science ®Google Scholar
• Wang L, Lawrence MS, Wan Y, et al. SF3B1 and other novel cancer genes in chronic lymphocytic leukemia. N Engl J Med. 2011;365:2497–2506.
   PubMed Web of Science ®Google Scholar
• Rossi D, Bruscaggin A, Spina V, et al. Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood. 2011;118:6904–6908.
   PubMed Web of Science ®Google Scholar
• Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012;158:426–429.
   PubMed Web of Science ®Google Scholar
• Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011–2015.
   PubMed Web of Science ®Google Scholar
• Tsimberidou AM, Keating MJ. Richter syndrome: biology, incidence, and therapeutic strategies. Cancer. 2005;103:216–228.
   PubMed Web of Science ®Google Scholar
• Rossi D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117:3391–3401.
   PubMed Web of Science ®Google Scholar