INTERNATIONAL JOURNAL OF ONCOLOGY 53: 7-20, 2018 Roles of STAT3 in leukemia (Review) YIN SHI1,2*, ZHEN ZHANG2*, XINTAO QU3*, XIAOXIAO ZHU2, LIN ZHAO2, RAN WEI2, QIANG GUO2, LINLIN SUN1,2, XUNQIANG YIN1,2, YUNHONG ZHANG1,2 and XIA LI2 1School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences; 2Laboratory for Molecular Immunology, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong 250062; 3Department of Bone and Joint Surgery Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China Received February 8, 2018; Accepted April 24, 2018 DOI: 10.3892/ijo.2018.4386 Abstract. Leukemia is a type of hematopoietic malignancy, 3. The role of STAT3 in the pathogenesis of leukemia and the incidence rate in the United States and European Union 4. The roles of STAT3 in the diagnosis, treatment and prognosis increases by an average of 0.6 to 0.7% annually. The incidence of leukemia rate in China is approximately 5.17/100,000 individuals, and 5. Conclusion the mortality rate is 3.94/100,000 individuals. Leukemia is the most common tumor affecting children and adults under 35 years of age, and is one of the major diseases leading to 1. Introduction the death of adolescents. Signal transducer and activator of transcription 3 (STAT3) is a vital regulatory factor of signal Leukemia, a common hematological malignancy, originates transduction and transcriptional activation, and once activated, from clonal leukemia cells with uncontrolled proliferation, the phosphorylated form of STAT3 (p-STAT3) is transferred blocked cell apoptosis and differentiation disorders. Leukemia into the nucleus to regulate the transcription of target genes, is characterized by accumulations of immature leukemic blasts and plays important roles in cell proliferation, differentiation, in the bone marrow and hematopoietic tissues, infiltration of apoptosis and other physiological processes. An increasing non-hematopoietic tissues and organs, and inhibition of normal number of studies have confirmed that the abnormal activa- hematopoietic function. The incidence of leukemia is increasing tion of STAT3 is involved in the development of tumors. In at an average rate of 0.7% annually in children and adolescents this review, the roles of STAT3 in the pathogenesis, diagnosis, of the United States; in China the incidence of leukemia is treatment and prognosis of leukemia are discussed in the approximately 5.17/100,000 individuals and the mortality aspects of cell proliferation, differentiation and apoptosis, with rate is 3.94/100,000 individuals, which severely endangers the aim to further clarify the roles of STAT3 in leukemia, and the lives of patients (1,2). There are several types of leukemia, shed light into possible novel targets and strategies for clinical and these can be divided into four common types according diagnosis and treatment. to cell morphology and biochemical characteristics as follows: Acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML) and chronic Contents myeloid leukemia (CML) (3). The pathogenesis and clinical treatment for leukemias are ‘hot’ and difficult research direc- 1. Introduction tions in the field of cancer. STAT proteins (STATs) belong to a 2. The structure and regulation of the activity of STAT3 family of transcription factors that are activated by polypeptide ligands, such as cytokines and growth factors. STATs comprise seven members: STAT1, STAT2, STAT3, STAT4, STAT5 (a/b) and STAT6 (4). STAT3 is a crucial member of the STAT family, which forms a dimer following activation, enters the nucleus, Correspondence to: Professor Xia Li, Laboratory for Molecular and regulates the transcription of diverse target genes (5,6). Immunology, Institute of Basic Medicine, Shandong Academy of Since it is closely associated with cell proliferation, differ- Medical Sciences, 18877 Jingshi Road, Jinan, Shandong 250062, entiation and apoptosis, its abnormal expression and activity P.R. China E-mail: [email protected] are involved in the development of certain diseases, such as hyper-IgE syndrome and developmental abnormalities (7). An *Contributed equally increasing number of studies have found that STAT3 abnormal expression and activation are accompanied by leukemia devel- Key words: signal transducer and activator of transcription 3, opment, which indicates the potential role of STAT3 in the leukemia, pathogenesis, prognosis, STAT3-directed therapy pathogenesis of leukemia (8-11). The present review focuses on the roles of STAT3 in the pathogenesis, diagnosis, treatment and prognosis of different types of leukemia. 8 SHI et al: ROLES OF STAT3 IN LEUKEMIA 2. The structure and regulation of the activity of STAT3 types of regulating factors, including the suppressor of cyto- kine signaling (SOCS) and the protein inhibitor of activated The structure of STAT3. The STAT3 encoding gene is located STAT (PIAS), which regulate the active status of STAT3 on the human genome chromosome 17 (17q21.1) and the through different mechanisms (28). These activation pathways protein contains six classical functional segments of the STAT and regulatory factors regulate STAT3 activity and function family: i) N-terminal domain (ND), which is able to stabilize synergistically, and play essential roles in physiological and the dimerized STAT3 and promote the formation of tetramers pathological processes (29-31) (Fig. 2). A description of these of two STAT3 dimers to make it more stable with DNA (12); activation pathways and regulatory factors is provided as ii) coiled-coil domain (CCD), which mediates STAT3 direct follows: binding to the receptor and facilitates STAT3 phosphoryla- a) The JAK/STAT3 pathway. The Janus kinase (JAK) family tion on 705-tyrosine site (Y705) (13); iii) DNA binding consists of four non-receptor tyrosine kinases, JAK1, JAK2, domain (DBD), which, by recognizing the γ-interferon acti- JAK3 and tyrosine kinase 2 (TYK2), which not only phos- vating sequence (GAS), will direct STAT3 to the promoters phorylate the bound cytokine receptors, but also a number of of target genes, and initiate transcriptional activation of the signaling molecules, which contain specific SH2 domains (32). target genes (14); iv) the linker region, the function of which Different cytokine receptors on the cell membrane bind the unknown at present; v) Src homology 2 (SH2) domain, the corresponding ligands to form homologous or heterodimers, most conserved part of STAT3, which shares the same core which drive the mutual phosphorylation of the JAKs in prox- sequence ‘GTFLLRFSS’ with the SH2 domain of tyro- imity and facilitate the activation of STAT3 (33-38) (Table I). sine kinase Src, and the phosphorylation and subsequent Mechanistically, the activated JAKs will phosphorylate tyro- dimerization of SH2 domain and plays a critical role in the sine residues on the receptor, which provides a ‘docking site’ process of signal transduction (15); vi) C-terminal transcrip- with the surrounding amino acid sequence for STAT3 protein tional activation domain (TAD), in which there are several recruitment by SH2 domain. Subsequently, STAT3 protein important tyrosines/serines located or near the region, and is phosphorylated by JAKs predominantly at the Y705 site, the phosphorylation of specific residues are important for leading to the activation and dimerization of STAT3, which will STAT3 function. For example, Y705 is located between SH2 rapidly enter the nucleus, specifically bind to the GAS sequence and TAD, which is crucial for STAT3 activation and dimer- (TTC/ANNNG/TAA) or the interferon-stimulated response ization, and the 727-serine site (S727) is located in TAD, element sequence (AGTTTCNNTTCNC/T), and initiate the which is thought to enhance the transcriptional activity of activation and transcription of target genes (13,39,40). In addi- STAT3 (16-18) (Fig. 1A). tion, the activity of STAT3 in the nucleus needs to be tightly STAT3 has four isoforms: STAT3α, STAT3β, STAT3γ and controlled. For example, STAT3 activity can be ‘shut down’ STAT3δ. Among the structures of STAT3 isoforms, STAT3α by the dephosphorylation effects of tyrosine phosphatase in is the most common structure. It consists of the ND, CCD, the nucleus, or by proteolytic enzyme degradation of STAT3 DBD, Linker, SH2 and TAD domains, with a molecular weight protein. of approximately 92 kDa, and is mainly associated with cell b) The Ras-MAPK activation pathway. The role of Ras proliferation and transformation (19,20) (Fig. 1A). STAT3β signaling in STAT3 activation has been demonstrated by originates from the alternative splicing of the STAT3 gene numerous studies, whereby the Ras-induced activation of transcript, which results in a 55 amino acid deletion at the MAPKs and the subsequent MAPK-mediated phosphorylation 3' end of the open reading frame of STAT3α with a molecular of STAT3 may be required for STAT3 activity (41). The MAPK weight of approximately 83 kDa; STAT3β lacks the C-terminal family includes extracellular signal-regulated kinases (ERKs), transactivation domain and S727, and acts as a dominant c-Jun N-terminal kinase (JNK) and p38 MAPK (p38), transcriptional inhibitory factor that is particularly crucial which act as components in the Ras signaling pathway with for granulocyte colony-stimulating factor (G-CSF)-mediated serine/threonine protein kinase activity (27). STAT3 is one of cell differentiation (21-23) (Fig. 1B). STAT3γ, with molecular the MAPK substrates, and