Biopolym. Cell. 2019; 35(1):30-38.
The STAT5 transcription factor in B-cells of patients with chronic lymphocytic leukemia
1Matvieieva A. S., 1Kovalevska L. M., 1Ivanivska T. S., 2Klein E., 1, 2Kashuba E. V.
  1. R. E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine
    45, Vasilkivska Str., Kyiv, Ukraine, 01022
  2. Karolinska Institutet
    Stockholm SE-171 77, Sweden


Aim. To find out the cause of inhibition of the IL2-STAT5 signaling pathway in chronic lymphocytic leukemia (CLL) cells. Methods.CLL cells were isolated from peripheral blood, using gradient centrifugation on a ficoll-verografin mixture. Expression of the STAT1-6 genes at the mRNA level was analyzed, using the Oncomine database. Expression, phosphorylation status and cellular localization of the STAT5 protein were studied by fluorescence microscopy, using specific antibodies. Results.Unlike B-cells of healthy donors, expression of the STAT5A protein was low in the patient CLL cells. As we have previously shown, the IL-2-STAT5 (JAK-STAT5) signaling pathway is inhibited in CLL cells. Now we demonstrated a low level of phosphorylation of the STAT5 protein, or a complete lack of phosphorylation in CLL cells. The STAT5A protein shows cytoplasmic localization, indicating the absence of complexes in the nucleus that activate/repress transcription of the STAT5-dependent genes. Conclusions. Inhibition of the IL-2-STAT5 pathway in CLL cells is caused by a lack of the STAT5 proteins phosphorylation and/or the absence of the active STAT5A transcription complexes in the nucleus of CLL cells.
Keywords: Chronic lymphocytic leukemia (CLL), B-peripheral blood cells, STAT5, STAT5A, STAT5B, IL2-STAT5 signaling pathway


[1] Muller-Hermelink HK ME, Catovsky D et al, editor. Cronic lymphocytic leukemia. small lymphocytic lymphoma. Lyon: IARC; 2008.
[2] Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277-300.
[3] Gluzman DF, SklyarenkoLM, Nagornaya VA Diagnostic oncohematology. 2003; Kiev: DIA; 256 p.
[4] Scarfò L, Dagklis A, Scielzo C, Fazi C, Ghia P. CLL-like monoclonal B-cell lymphocytosis: are we all bound to have it? Semin Cancer Biol. 2010;20(6):384-90.
[5] Bandobashi K, Liu A, Nagy N, Kis LL, Nishikawa J, Björkholm M, Klein G, Klein E. EBV infection induces expression of the transcription factors ATF-2/c-Jun in B lymphocytes but not in B-CLL cells. Virus Genes. 2005;30(3):323-30.
[6] Klein E, Nagy N. Restricted expression of EBV encoded proteins in in vitro infected CLL cells. Semin Cancer Biol. 2010;20(6):410-5.
[7] Ravandi F, Talpaz M, Kantarjian H, Estrov Z. Cellular signalling pathways: new targets in leukaemia therapy. Br J Haematol. 2002;116(1):57-77. Review.
[8] Matvieieva AS, Kovalevska LM, Polishchuk OS, Mushtag M, Kashuba EV. Expression profile of transcription factors in the blood samples of patients with the chronic lymphocytic leukemia. Oncology. 2016; 18 (4): 311-5.
[9] Matveeva A, Kovalevska L, Kholodnyuk I, Ivanivskaya T, Kashuba E. The TGF-beta - SMAD pathway is inactivated in cronic lymphocytic leukemia cells. Exp Oncol. 2017;39(4):286-290.
[10] Matveeva A, Kovalevska L, Polischuk A, Kashuba E. The IL-2-STAT5 pathway is blocked in chronic lymphocytic leukemia cells. Oncology. 2017; 19(4): 247-53.
[11] Matvieieva A, Kovalevska L, Kashuba E. The SMAD4 transcription factor shows cytoplasmic retention in B-cells of patients with chronic lymphocytic leukemia (CLL). Factors in experimental evolution of organisms. 2018; 22: 144-8.
[12] Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-11.
[13] Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, López-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937-47.
[14] Basso K, Margolin AA, Stolovitzky G, Klein U, Dalla-Favera R, Califano A. Reverse engineering of regulatory networks in human B cells. Nat Genet. 2005;37(4):382-90.
[15] Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Béné MC, De Vos J, Hernández JM, Hofmann WK, Mills KI, Gilkes A, Chiaretti S, Shurtleff SA, Kipps TJ, Rassenti LZ, Yeoh AE, Papenhausen PR, Liu WM, Williams PM, Foà R. Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: report from the International Microarray Innovations in Leukemia Study Group. J Clin Oncol. 2010;28(15):2529-37.
[16] Weber-Nordt RM, Egen C, Wehinger J, Ludwig W, Gouilleux-Gruart V, Mertelsmann R, Finke J. Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. Blood. 1996;88(3):809-16.
[17] Malin S, McManus S, Busslinger M. STAT5 in B cell development and leukemia. Curr Opin Immunol. 2010;22(2):168-76. Review.
[18] Malin S, McManus S, Cobaleda C, Novatchkova M, Delogu A, Bouillet P, Strasser A, Busslinger M. Role of STAT5 in controlling cell survival and immunoglobulin gene recombination during pro-B cell development. Nat Immunol. 2010;11(2):171-9.
[19] Mitra A, Ross JA, Rodriguez G, Nagy ZS, Wilson HL, Kirken RA. Signal transducer and activator of transcription 5b (Stat5b) serine 193 is a novel cytokine-induced phospho-regulatory site that is constitutively activated in primary hematopoietic malignancies. J Biol Chem. 2012;287(20):16596-608.
[20] Heltemes-Harris LM, Farrar MA. The role of STAT5 in lymphocyte development and transformation. Curr Opin Immunol. 2012;24(2):146-52.
[21] Wingelhofer B, Neubauer HA, Valent P, Han X, Constantinescu SN, Gunning PT, Müller M, Moriggl R. Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia. 2018;32(8):1713-1726.