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Journal of Clinical Oncology, Vol 22, No 2 (January 15), 2004: pp. 361-371 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.124
The Role of Signal Transducer and Activator of Transcription Factors in LeukemogenesisFrom the Brigham and Women's Hospital, Harvard Medical School, and Howard Hughes Medical Institute, Boston, MA Address reprint requests to David W. Sternberg, MD, PhD, Hematology Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115; e-mail: dsternberg{at}partners.org
Human leukemias are frequently associated with the aberrant expression of activated fusion tyrosine kinases or activated protein tyrosine kinases carrying insertional or point mutations. The activated kinase enzymes typically phosphorylate one or more signal transducer and activator of transcription (STAT) factors, which translocate to the cell nucleus and regulate the expression of genes associated with survival and proliferation. The phosphorylation and activation of STAT family members has been described in a wide range of human leukemias. Furthermore, animal models of leukemia have demonstrated the pivotal contribution of STAT activation to leukemic pathogenesis. This review discusses evidence for the functional importance of STAT activation in the biology of leukemia and current opportunities for modulating STAT proteins in the therapy of this group of diseases.
A common theme in the understanding of the molecular events that underlie carcinogenesis is the use of normal signaling pathways by rogue protein products of oncogenes. Normal signaling cascades that allow a cell to sense extracellular triggers are usurped by oncogene products to stimulate inappropriate cell proliferation, halt differentiation, and prevent programmed cell death. Numerous families of molecules couple extracellular signaling to the control of gene expression [1], and these molecules are either engaged by oncogene products or are themselves activated by mutation or by overexpression. Signal transducer and activator of transcription (STAT) proteins comprise a family of signaling molecules that mediate the control of gene expression in response to extracellular stimuli, and the activation of these molecules is a recurring feature of malignancies of both hematopoietic and nonhematopoietic origin. This review presents the recent understanding of the role of STAT transcription factors in leukemogenesis. A number of excellent reviews are available that discuss the role of STATs in cytokine signaling [2], in oncogenesis [3–5], in leukemogenesis [6–8], and as novel targets for drug therapy in malignancy [9–11]. This discussion focuses on recent functional evidence for the importance of STAT activation in cell culture and whole animal models of leukemia, the role of STAT activation in human leukemogenesis, and the potential utility of modifying STAT activity in the clinical management of leukemia. Members of the STAT family of signal transducers were first identified as transcription factors that were activated in response interferon stimulation [12–14]. STAT transcription factors are also activated by ligand binding to cytokine receptors and to growth factor receptor tyrosine kinases, such as the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) [15]. These growth factor receptors can phosphorylate STATs directly or indirectly through activation of cytoplasmic tyrosine kinases, such as the c-src product. Thus, activation of STATs is a common element in the cellular response to cytokine and growth factor stimulation. Mammalian organisms have seven STAT genes (STAT 1, 2, 3, 4, 5a, 5b, and 6), which are clustered in three chromosomal regions [15]. The STATs share common structural features that are functionally important for their regulation. Each consists of an aminoterminal DNA binding domain and a carboxyterminal transactivation domain that stimulates transcription when the STAT is bound to a DNA regulatory element. Also within the carboxyterminal half of the STAT protein is a consensus site for tyrosine phosphorylation and an SH2 (src-homology-2) domain that specifically recognizes phosphorylated protein tyrosine residues. When a cytokine binds to its respective receptor, the receptor dimerizes and results in activation of constitutively associated members of the Janus kinase (JAK) family of tyrosine kinases (Fig 1). The JAK family of kinases consists of four members in mammalian organisms (JAK1, JAK2, JAK3, and TYK2). The JAKs are activated by cross-phosphorylation, and the JAKs then phosphorylate the intracellular domains of the cytokine receptor. STAT proteins residing in the cytoplasm bind to the phosphorylated cytokine receptor subunits through their respective SH2 domains, and the STATs in turn are phosphorylated at the carboxyterminal tyrosine residue. Growth factor receptors such as EGFR and PDGFR have intrinsic protein tyrosine kinase activity and can phosphorylate STATs directly. Alternatively, the growth factor receptors can phosphorylate STAT by recruiting nonreceptor type src-family tyrosine kinases [16]. Moreover, the SRC protein has been reported to mediate activation of STATs during IL3 receptor activation, and this finding indicates that cytokine receptor signaling might in some instances be transmitted by SRC-family tyrosine kinases rather than by JAKs [17–19]. In cells that express leukemic tyrosine kinases, such as BCR-ABL of chronic myelogenous leukemia or activated FLT3 of acute myelogenous leukemia, the activated protein tyrosine kinase expression leads to STAT phosphorylation and activation in a manner that is independent of ligand stimulation (Fig 1).
Through each of these phosphorylation mechanisms, the tyrosine phosphorylation of STATs facilitates their homotypic dimerization through SH2 binding of one molecule to the phosphotyrosine residue of the other. Moreover, distinct STAT molecules can heterodimerize after tyrosine phosphorylation. The combinatorial complexity of STAT homodimerization and heterodimerization allows for a broad repertoire of biologic responses to extracellular regulatory cues. Dimerization of STATs results in their translocation to the nucleus, where they bind to specific DNA regulatory elements and thereby alter the profile of gene expression.
In some instances, the activity of the STAT transcription factor can be further modulated by the phosphorylation of the STAT protein on a serine residue. Gamma interfereon (IFN-
More recently, protein methylation has been shown to regulate the activity of at least one member of the STAT family. IFN STAT5a and STAT5b are also regulated post-translationally to generate carboxyterminal truncated derivatives that are functionally dominant-negative [29–33]. Both isoforms have been reported to be cleaved by a serine protease, and this carboxyterminal truncation may play a role in the regulation of myeloid differentiation. A candidate molecule with such activity is the calpain cysteine protease, which has been purified from platelets and cleaves STAT5 and STAT3 both in vivo and in vitro [34]. Several widely used assays for STAT covalent modification and activation are available. STAT proteins can be assayed for tyrosine or serine phosphorylation by immunoblot of protein extracts with commercially available antibodies against phosphotyrosine or against specific phosphopeptide motifs. Although this assay provides a facile means of determining STAT phosphorylation, it is not a direct measure of STAT functional activity. STAT translocation to the nuclear compartment can be determined by immunofluorescent methods using antibodies directed against STAT proteins, and confocal microscopy can increase the precision of imaging. A more direct assay for STAT activation is the determination of protein binding to DNA in an electrophoretic mobility shift assay (EMSA); STAT proteins from nuclear extracts are bound to radiolabeled oligonucleotide probes that correspond to STAT-specific DNA-binding motifs. Functional activation of STAT transcriptional activity can be determined by transfecting cells with a STAT-specific promoter fused to a reporter gene (such as firefly luciferase); expression of the reporter transgene is thus a direct measure of STAT-dependent transcriptional activity.
Evidence for STAT Activation in Leukemias
Biethahn et al [40] have assessed the expression of JAKs and STATs in normal human myeloid cells at various stages of maturation and in blasts from patients with acute myelogenous leukemia. CD34+ cells from normal healthy donors expressed each of the known JAK proteins (JAK1, JAK2, JAK3, and TYK2) and STAT1, STAT3, STAT5a, and STAT5b. Each of the JAK and STAT proteins was markedly diminished or absent in granulocyte precursors and in mature neutrophils. The expression pattern of these proteins was assessed also in leukemic blasts from 24 patients with newly diagnosed AML or in one patient with a myelodysplastic syndrome (RAEB-T). Expression of JAK kinases was heterogeneous in this series, but each of the samples expressed at least one of the JAK proteins. Absence of one or more JAK proteins was observed particularly in blasts with an abnormal karyotype. In contrast, the blasts of each of these patients expressed STAT1 and STAT3 (although one patient did not express the STAT1  isoform). STAT5 was found to be expressed in 21 of 25 patients. Thus, the various JAK tyrosine kinases may have a redundant or unnecessary function in the survival and proliferation of blasts from some AML patients. Phosphorylation of STAT proteins by expression of an activated FLT3 tyrosine kinase in 20% to 30% of AML cases [41–45] may substitute for JAK kinase expression in these cells (discussed further in this article). Interestingly, the tyrosine phosphatase SHP-1 was shown to be expressed in the blasts of all AML patients in this series. SHP-1 is a negative regulator of the JAK/STAT signaling pathway [46,47]. Moreover, deficiency of SHP-1 in mice causes hyperactivation of cytokine responses and myeloproliferative disease. Thus, the report by Biethahn et al indicates that the absence of SHP-1 expression is not necessary for the development of AML, although this finding does not exclude a cryptic functional inhibition of SHP-1 phosphatase activity in leukemic blasts. This group has extended these results by exploring the activation of STAT proteins in a variety of human AML cell lines by immunoblotting STAT phosphotyrosine [48]. Three patterns of STAT activation were observed: activation of STAT1 alone, activation of STAT1 and STAT3, or activation of STAT1, 3, and 5. Phosphorylation of the JAK kinases could not be detected, although it is not clear whether this was due to insufficient sensitivity of detection or to engagement of STATs by other activated tyrosine kinases in these leukemias. However, the functional importance of the JAK/STAT pathway was supported by the treatment of these cell lines with the tyrphostin drug AG490, which inhibits JAK2 protein tyrosine kinase activity but does not inhibit other tyrosine kinases, such as LCK, LYN, BTK, SYK, and SRC [49]. The proliferation of each of the human AML cell lines that expressed JAK2 was inhibited by AG490 in a dose-dependent manner. Schuringa et al [50] have reported that STAT3 tyrosine 705 and serine 727 phosphorylation occurred in five of 20 patients (25%) with AML, and the phosphorylation on both residues may be dependent on autocrine stimulation by IL-6 expression in leukemic cells. Thus, activation of the JAK/STAT pathway is a recurring event in the pathogenesis of AML.
The role of STAT3 activation in AML has been studied by Benekli et al [51] in 50 patients with de novo AML and 13 patients with secondary AML; these authors used both phosphotyrosine immunoblot and EMSA methods to determine STAT activation. Constitutive activation of STAT3 was identified in 28 of 63 patients (44%) with AML. Patients whose blasts exhibited constitutive STAT3 activation had significantly reduced disease-free survival. This difference persisted after controlling for primary versus secondary AML, age, and karyotype. Surprisingly, patients whose blasts expressed STAT3ß (a carboxyterminal-truncated isoform that is a dominant-negative inhibitor of STAT3 LIL-STAT was initially described as a STAT transcription factor that bound to the lipopolysaccharide/interleukin-1ß (IL-1ß)-responsive element (LILRE) sequence motif [52]. LIL-STAT was subsequently shown to consist of a heterodimer of STAT1 and STAT3 subunits [53]. In a series of seven patients with adult T-cell leukemia, all patient samples were found to contain activated LIL-STAT by EMSA [54]. Moreover, seven of nine AML samples demonstrated activation of LIL-STAT by EMSA [55]. The coordinate regulation of STAT proteins by tyrosine phosporylation and serine/threonine kinase activation in AML samples was examined by Hayakawa et al [56]. In 50 patient samples with previously demonstrated ERK serine/threonine kinase activation, 40 of 50 samples (80%) showed tyrosine phosphorylation of STAT5 isoforms. Seventeen of 23 specimens examined showed STAT3 tyrosine phosphorylation. The activation of ERK was found to be independent of STAT3 and STAT5 DNA binding and tyrosine phosphorylation. However, as discussed previously herein, it remains possible that in some cases the activation of STAT proteins is modified through serine phosphorylation by ERK or by other kinases. STAT activation has also been demonstrated in chronic myelogenous leukemias by phosphotyrosine immunoblot and EMSA assays. Both STAT1 and STAT5 have been reported to be activated in cell lines derived from p185 and p210 BCR-ABL-positive leukemias [57–59]. Thus, in addition to the poorly differentiatied myelogenous leukemias discussed previously, the more differentiated cells of chronic myelogenous leukemia (CML) exhibit STAT activation. The activation of STATs by the BCR-ABL gene product will be discussed further in this article. Frank et al [60] examined the phosphorylation of STAT proteins in chronic lymphocytic leukemia (CLL). Interestingly, none of the STAT transcription factors was found to be tyrosine phosphorylated in any of the 32 CLL samples. In contrast, all of the CLL leukemia cells showed serine phosphorylation of STAT1 and STAT3. Although the functional importance of carboxyterminal serine phosphorylation in CLL remains to be demonstrated, this report suggests that activation of one or more serine/threonine kinases rather than tyrosine kinase activation is pertinent to STAT activation in CLL. These findings collectively underscore the complexity of STAT signaling in normal growth factor and cytokine signaling and in the pathogenesis of leukemia. There is the potential for regulation of STAT tyrosine phosphorylation and nuclear transport, modulation of the stoichiometry of STAT homodimerization and heterodimerization, further post-translational modification by serine phosphorylation or arginine methylation, and the contribution of other modifiers of STAT-specific responses that are specific for each cellular context.
STATs in Signaling by Leukemic Fusion Proteins
In chronic myelomonocytic leukemia (CMML), the recurring chromosomal translocation t(5;12) was characterized and was found to encode a fusion of the aminoterminal domain of the TEL DNA-binding protein and the cytoplasmic domain of the platelet-derived growth factor receptor-ß (PDGFßR) receptor tyrosine kinase [71]. The PNT domain of TEL mediates homotypic oligomerization of the PDGFßR catalytic domain and constitutive activation of the tyrosine kinase [72,73]. Oligomerization of protein tyrosine kinases and cross-phosphorylation is a common event in the activation of this family of signaling molecules [74]. Just as the native PDGFßR has been shown to induce the phosphorylation and DNA-binding of multiple STATs and JAK kinases [75], the TEL/PDGFßR fusion protein coopts this signaling pathway and is able to cause constitutive STAT tyrosine phosphorylation [76]. These findings have been extended to show that STAT5 activation cooperates with activation of phosphoinisitide 3-kinase (PI 3-kinase) and phospholipase C-
Leukemic fusions can also co-opt JAK-STAT signaling components by incorporating them directly into the activated fusions as a result of chromosomal translocation. One striking example of this is the fusion of STAT5b to the retinoic acid receptor Another example of direct recruitment of the JAK-STAT signaling components in leukemic fusion proteins is the fusion of TEL with the JAK2 tyrosine kinase. TEL-JAK2 fusions have been described in a patient with a t(9;15;12) atypical CML and from two patients with t(9;12) T-cell ALL and pre-B-cell ALL [87,88].
STATs in Signaling by FLT3 and Other Activated Tyrosine Kinases The activated form of the FLT3 tyrosine kinase, which is associated with internal tandem duplications of the juxtamembrane domain or activation loop point mutations, has been observed in 20% to 30% of patients with acute myelogenous leukemia and confers a poor prognosis for patients with this disease [41,42]. These FLT3 mutations are associated with STAT5 tyrosine phosphorylation and DNA-binding [43,44], and one report [45] has indicated that STAT5a but not STAT5b is a critical target for FLT3-mediated proliferation of murine hematopoetic cells.
Animal Models for the Role of STATs in Leukemogenesis The role of STAT1 in the pathogenesis of leukemias derived from tyrosine kinase fusion proteins was addressed using these STAT1 knockout mice. Bone marrow from wild-type or STAT1-deficient mice was extracted, transduced ex vivo with a retrovirus that encoded the fusion tyrosine kinase of interest, and then injected into lethally-irradiated congenic recipient mice. Thus, hematopoiesis was reconstituted in the recipient mice with hematopoietic progenitor cells that expressed the leukemic tyrosine kinase but were deficient for STAT1 expression. When STAT1-deficient mice were transduced with the BCR-ABL fusion gene, the recipient mice developed a rapidly fatal myeloproliferative disease identical to that caused by BCR/ABL-transduced wild-type bone marrow [4], and this result indicates that STAT1 is dispensible for the generation of leukemia by BCR/ABL. Similarly, transduction of STAT1-deficient bone marrow with the TEL/JAK2 fusion gene was able to cause a myelo- and lymphoproliferative disease in recipient mice similar to that elicited using wild-type bone marrow [98,99]. STAT5 is activated in response to numerous cytokines, and the use of mice deficient in STAT5a and STAT5b has provided functional evidence for the role of these signaling molecules in leukemogenesis. STAT5a-deficient mice show impairment of mammary gland development and lactogenesis [100], and STAT5b-deficient mice show partial loss of growth hormone functional responses [101]. Disruption in the mouse of either STAT5a or STAT5b causes no apparent deficiency of hematopoiesis, and these two STAT5 isoforms might serve redundant roles in the hematopoietic development. However, STAT5a-/-STAT5b-/- double knockout mice have selective impairments in hematopoietic in vitro colony assays and in vivo repopulation assays [102,103] and have an impaired response to erythropoietic stress [104,105]. These STAT5a/b-double knockout mice have served as useful models to understand the role of STAT5-activation in leukemogenesis. In the murine transplant model described, transduction of bone marrow derived from STAT5a/b-double null mice with the BCR/ABL fusion gene is able to confer a rapidly fatal myeloproliferative disease, as does transduction with the v-Abl gene [106]. These results are in contrast to those involving transduction with the TEL/JAK2 fusion gene, which is able to cause a mixed myelo- and lymphoproliferative disease in recipient mice. STAT5a/b-null bone marrow transduced with the TEL/JAK2 fusion gene is unable to generate a myelo- or lymphoproliferative disease in recipients [99]. STAT5a expression from the retroviral construct is able to rescue the mixed myelo- and lymphoproliferative disease induced by TEL/JAK2 expression. Moreover, expression of a mutated constitutively active STAT5a allele is sufficient to generate a myeloid leukemia in transduced mice. Thus, there is a variable requirement for STAT5 in the pathogenesis of myeloid leukemias induced by activated tyrosine kinases, and TEL/JAK2 defines one class of fusion genes that requires STAT5 function for the generation of hematopoietic disease. One transcriptional target of STAT5 is oncostatin M [107], a cytokine that can regulate the production of granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) [108]. Overexpression of bovine oncostatin M in transgenic mice causes multiple hematopoietic abnormalities, including splenomegaly, expansion of the megakaryocyte population in the bone marrow, and lymphadenopathy [109]. Moreover, in the murine bone marrow transplant model, oncostatin M was able to cause a myeloproliferative disease similar to that caused by activated STAT5a or by TEL/JAK2 expression [99]. Taken together, these results provide correlative evidence for the role of oncostatin M as a target of STAT5 in leukemia induced by TEL/JAK2. Another target of STAT5 is the antiapoptotic molecule Bcl-X [105,110–112]. Interestingly, JAK2 has been reported to mediate erythropoetin-stimulated BcL-X expression independent of STAT activation [113]. However, in contrast to the retroviral transduction of oncostatin M, expression of Bcl-X in the murine bone marrow transplant model is unable to cause disease after at least 9 months of observation [99].
STATs As Therapeutic Targets in Leukemia In addition to the development of tyrosine kinase inhibitors that are directed against leukemic tyrosine kinases, selective JAK kinase inhibitors have been developed as well. Leukemic blasts from patients with ALL in relapse have been shown to have activated JAK2 tyrosine kinase activity, and the selective JAK2 inhibitor AG490 blocks growth of these cells in vitro by inducing apoptosis [49]. At comparable concentrations of this inhibitor normal hematopoiesis is not affected. Moreover, infusion of AG490 into SCID mice that were injected with these ALL cells suppressed the propagation of the leukemia cells [49]. Other B-precursor cell lines, including those that contain an 11q23 rearrangement or the Philadelphia chromosome, are sensitive to AG490 treatment [119]. These findings have been extended to other leukemia models. The Se-Ax cell line derived from a patient with Sezary syndrome has constitutive activation of STAT3, and treatment of these cells with the JAK2 inhibitor AG490 induces apoptosis [120]. The effect of AG490 in combination with STI571 has been assessed in a BCR-ABL-positive derivative of FDC-P1 cells [121]. AG490 synergizes with STI571 to inhibit cell proliferation driven by the BCR-ABL tyrosine kinase. Marley el al [122] recently reported the sensitivity of primary leukemic cells from 55 patients with chronic-phase CML to the combination of STI571 and AG490, and they observed an additive effect of these two agents on inhibition of cell proliferation. These findings together suggest that AG490 might be effective in the treatment of some patients who develop resistance to STI571 alone. In addition to direct targeting of leukemic signaling molecules by JAK inhibitors, these agents may have utility as immune modifiers in stem cell transplantation. In a murine bone marrow transplant model, mice were challenged with a lethal dose of BCL-1 leukemia cells, and they were then treated by bone marrow transplantation with an allogeneic graft [123]. The probability of survival at day 30 was increased from 11% to 63% by treatment of the mice with the JAK3 inhibitor WHI-P131/JANEX-1. The increased survival was not due to a direct effect of the drug on the BCL-1 cells, because these leukemia cells are insensitive to the effects of this agent. Rather, the increased survival was attributable to a decreased incidence of GVHD-associated deaths [123,124].
Multiple lines of evidence from cell culture models, whole animal models, and biochemical analyses of patient materials have indicated the central role of STAT activation in the pathogenesis of many forms of leukemia. Molecular profiling of STAT activity in human leukemias might be of use in the diagnosis of such diseases, and an understanding of the STAT activity profile might guide the selection of a particular therapeutic intervention in each patient. Furthermore, STAT proteins might themselves serve as rational targets for chemotherapeutic intervention. The development of protein tyrosine kinase inhibitors that attenuate the phosphorylation of STAT proteins (as well as other cellular targets) has been a significant advance in the treatment of neoplasia. Selective inhibition of STAT proteins might also serve as an effective antileukemic therapy, although it is not yet clear whether such a strategy would be as effective as direct inhibition of activated protein kinases. The use of small molecule inhibitors of STAT protein function might have therapeutic activity. The modulation of STAT expression using ribozyme or RNA interference strategies might also be effective, although the delivery of such agents to all leukemic cells would pose a significant challenge. Direct STAT modulation might serve as one component of a multiagent attack on signaling targets in leukemia, and such a combinatorial approach might prevent the emergence of drug resistant leukemic cells. The selective modulation of STAT proteins may emerge as a core component of antileukemic therapies that are guided by the understanding of cellular signaling.
Authors' Disclosures of Potential Conflicts of Interest
Supported by National Institutes of Health grant CA82261 (D.W.S.), and National Institutes of Health grants CA66996 and DK50654; a grant from the Leukemia and Lymphoma Society; and the Howard Hughes Medical Institute (D.G.G.). Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
) treatment can lead to phosphorylation of STAT1 on both tyrosine and serine residues; STAT1 serine phosphorylation does not require prior tyrosine phosphorylation, and the phosphorylation on serine is independent of RAS/mitogen activated protein kinase signaling [
