EPIGENETIC MECHANISMS OF TUMOR PROGRESSION IN CHRONIC LYMPHOID LEUKEMIA

Author: Basharova R.R.¹, Agakishiev M.M.², Berezina O.V.³, Kovynev I.B.⁴, Pospelova T.I.⁵

Abstract

The data on studies of the expression of microRNA regulatory molecules miR-155 and miR-223 in bone marrow and peripheral blood cells in patients with chronic lymphoid leukemia (CLL) at various stages of the disease progression are presented. The microRNAs were determined by the method of highly sensitive PCR in various peripheral blood substrates (plasma, lymphocytes, extracellular vesicles) and bone marrow in patients with CLL. The expression rates correlated with clinical data and the effectiveness of standard therapy. It is noted that an increase in the miR-155 expression and decrease in the miR-223 expression are associated with poor prognosis, resistance to therapy and high rate of the tumors progression of chronic lymphocytic leukemia. MiR-155 overexpression in all studied blood substrates (plasma, lymphocytes, extracellular vesicles) and bone marrow and decrease in miR-223 expression in lymphocytes, bone marrow and plasma were significantly associated with the stages of chronic lymphocytic leukemia according to J. Binet. The patients with CLL with the miR-223 low level in the bone marrow, extracellular vesicles and plasma and the miR-155 high level before treatment initiation did not achieve an optimal response to the therapy.

Key words

miR-155, miR-223, chronic lymphoid leukemia, tumor progression of lymphomas

References

Binet J.L., Leporrier M., Dighiero G., Charron D., D’Athis P., Vauqier G., Beral H.M., Natali J.C., Raphael M., Nizet B., Follezou J.Y. A clinical staging system for chronic lymphocytic leukemia: prognostic significance // Cancer. 1977. 40. (2). 855-864.

Calin G.A., Dumitru C.D., Shimizu M., Bichi R., Zupo S., Noch E., Aldler H., Rattan S., Keating M., Rai K., Rassenti L., Kipps T., Neqrini M., Bullrich F., Croce C.M. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia // Proc. Natl. Acad. Sci. USA. 2002. 99. (24). 15524–15529.

Ferrajoli A., Shanafelt T.D., Ivan C., Shimizu M., Rabe K.G., Nouraee N., Ikuo M., Ghosh A.K., Lerner S., Rassenti L.Z., Xiao L., Hu J., Reuben J.M., Calin S., You M.J., Manning J.T., Wierda W.G., Estrov Z., O'Brien S., Kipps T.J., Keating M.J., Kay N.E., Calin G.A. Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia // Blood. 2013. 122. (11). 1891-1899.

Gentner B., Pochert N., Rouhi A., Boccalatte F., Plati T., Berq T., Sun S.M., Mah S.M., Mirkovic-Hösle M., Ruschmann J., Muranyi A., Leierseder S., Arqiropoulos B., Starczynowski D.T., Karsan A., Heuser M., Hogge D., Camargo F.D., Enqelhardt S., Döhner H., Buske C., Jongen-Lavrencic M., Naldini L., Humphries R.K., Kuchenbauer F. MicroRNA-223 dose-levels fine-tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia // Exp. Hematol. 2015. 43. (10).

Glinge C., Clauss S., Boddum K., Jabbari R., Jabbari J., Risgaard B., Tomsits Ph., Hildebrand B., Kääb S., Wakili R., Jespersen Th., Tfelt-Hansen J. Stability of circulating blood-based microRNAs – pre-analytic methodological considerations // PLoS One. 2017. 1223. 446–452.

Hallek M., Cheson B.D., Catovsky D., Caliqaris-Cappio F., Dighiero G., Döhner H., Hillmen P., Keating M.J., Montserrat E., Rai K.R., Kipps T.J. 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. (12). 5446–5456.

Hurschler B.A., Ding X.C., Großhans H. MiRNA Regulation of the Translational Machinery // Progress in Molecular and Subcellular Biology. 2010. 50. 21–4.

Jing, Y., Juanmin Z. Correlation of Obesity and Osteoporosis: Effect of Free Fatty Acids on Bone Marrow-Derived Mesenchymal Stem Cell Differentiation // Experimental and Therapeutic Medicine. 2010. 1 (4). 603–610.

Kisilichina D.G., Lugovskaya S.A., Pochtar M.E., Naumova E.V., Biderman B.B., Sudarikov A.B., Nikitin E.A., Dolgov V.V. Peculiarities of evaluation of Zap-70 expression in tumor cells in B-cell chronic lymphocytic leukemia using the flow method. Klinicheskaya laboratornaya diagnostika = Clinical laboratory diagnostics. 2012. (6). 47-52. [In Russian].

Li J., Wan Y., Ji Q., Fang Y., Wu Y. The role of microRNAs in B-cell development and function // Cell. Mol. Immunol. 2013. 10. (2). 107–112.

Li S., Moffett H.F., Lu J., Werner L., Zhang H., Ritz J., Neuberg D., Wucherpfennig K.W., Brown J.R., Novina C.D. MicroRNA expression profiling identifies activated B cell status in chronic lymphocytic leukemia cells // PLoS One. 2011. 6.

O’Connell R.M., Zhao J.L., Rao D.S. MicroRNA function in myeloid biology // Blood. 2011. 118. (11). 2960–2969.

Poddubnaya I.V., Savchenko V.G. Russian clinical guidelines for the diagnosis and treatment of lymphoproliferative diseases. Moscow: Buki-Vedi, 2016. 324 p. [In Russian].

Roosbroeck K.V., Calin G.A. MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies? // Semin. Oncol. 2016. 43. (2). 209–214.

Schwarzenbach H., da Silva A.M., Calin G., Pantel K. Data normalization strategies for microRNA quantification // Clin. Chem. 2015. 61. (11). 1333–1342.

Stamatopoulos B., Meuleman, N., Haibe-Kains B., Saussoy P., Neste E.V.D., Michaux L., Heimann P., Martiat Ph., Bron D., Lagneaux L. MicroRNA-29c and MicroRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification // Blood. 2016. 113. (21). 5237–5246.

Vargova K. The role of oncogenic microRNA-155 and proto-oncogen MYB in chronic lymphocytic leukemia. Prague, 2013. 170 p.

Yeh Y.-Y., Ozer H.G., Lehman A.M., Maddocks K., Yu L., Johnson A.J., Byrd J.C. Characterization of CLL Exosomes Reveals a Distinct MicroRNA Signature and Enhanced Secretion by Activation of BCR Signaling // Blood. 2016. 125. (21). 3297–3306.

Zhang Y., Lin J., Huang W., Cao Y., Liu Y., Wang T., Zhong W., Wang D., Mao R., Chen X. The effect of circulating miR-223 on surveillance of different cancers: a meta-analysis // Onco Targets Ther. 2017. 10. 3193-3201.

Zhou H., Xiao J., Wu N., Liu C., Xu J., Liu F., Wu L. MicroRNA-223 regulates the differentiation and function of intestinal dendritic cells and macrophages by targeting C/EBPβ // Cell Rep. 2015. 13. (6). 1149–1160.

Zhou K., Yi S., Yu Z., Li Z., Wang Y., Zou D., Qi J., Zhao Y., Qiu L. MicroRNA-223 expression is uniformly down-regulated in B cell lymphoproliferative disorders and is associated with poor survival in patients with chronic lymphocytic leukemia // Leuk. Lymphoma. 2012. 53. (6). 1155-1161.

About Authors (Correspondence):

Basharova R.R. – resident of department of therapy, hematology and transfusiology, e-mail: post_gem@mail.ru

Full Text

snmzh_1-2019_basharova_66-71.pdf

Received: 27/02/2019

Accepted: 27/02/2019