STAT signaling in the pathogenesis and treatment of leukemias

Leukemias continue to cause significant mortality inadults and children, and the use of standard cytotoxicchemotherapy has reached a therapeutic plateau. Thus,there is great interest in treatments directed againstinappropriately activated cell signaling pathways whichstimulate the uncontrolled growth of neoplastic cells.Increasing evidence suggests that the STAT signalingcascade may be one target of these therapies. Signaltransducer and activator of transcription (STAT)proteins are critical in mediating the response ofhematopoietic cells to a diverse spectrum of cytokines.Constitutive STAT activation is present in manymalignancies and has been especially well characterizedin acute and chronic leukemias. While STAT activationis a common characteristic of leukemias, the specificpattern of activated STATs and the manner by whichSTAT activation occurs vary with each disease. STATtyrosine phosphorylation can occur through inappropri-ate Jak activation or by direct activation of anoncoprotein such as Bcr/Abl, and STAT serinephosphorylation may play an important role in leukemiasas well. Thus, the STAT signaling pathway is anattractive target for therapeutic intervention, andstrategies designed to inhibit STAT activation andSTAT mediated gene transcription may play animportant role in the next generation of anti-leukemiatherapies. Oncogene (2000) 19, 2496–2504.Keywords: STAT; cytokines; cancer; leukemia; therapyHuman leukemiasLeukemias comprise a heterogeneous group of clonalhematologic malignancies which continue to causesignificant mortality and morbidity despite decades ofresearch and drug development. Approximately 26 000patients are diagnosed with leukemia in the UnitedStates annually, and more than 20 000 adults andchildren die each year of their disease (Holland et al.,1997). Leukemias are classified as acute or chronic,depending upon their clinical development and ex-pected progression, and as lymphoid or myeloid,depending upon the lineage from which the cancerarises. The acute leukemias are characterized by arapidly progressive, fatal course if untreated, but thesediseases often respond to aggressive cytotoxic che-motherapy, especially in children and younger adults.Acute lymphocytic leukemia (ALL) a•ects bothchildren and adults, while acute myelogenous leukemia(AML) strikes predominantly adults. Although greatstrides in clinical response and long-term survival wereinitially achieved with the advent of chemotherapy inleukemia patients, particularly children, a plateau inclinical benefit has been reached with the use ofstandard forms of cytotoxic chemotherapy alone.In contrast to the rapidly progressive acuteleukemias, the chronic leukemias are indolent, oftenasymptomatic, diseases in which median survivalsoften measure several years. However, the chronicleukemias cannot be cured by standard chemotherapyand are invariably fatal in the absence of bonemarrow transplantation (BMT) (Lee et al., 1997;Rabinowe et al., 1993). Chronic lymphocytic leukemia(CLL), the most common leukemia in the Westernworld, generally a•ects older patients with a medianage of greater than 60 and is typically the mostindolent leukemia (Rozman and Montserrat, 1995).However, although chemotherapy can control CLLfor periods of time, no cure has been identified forCLL. Chronic myelogenous leukemia (CML) a•ects aslightly younger adult population (Sawyers, 1999).Although CML cannot be cured by standard cytotoxictherapy, younger patients with an HLA-identicalsibling or unrelated donor can undergo allogeneicBMT with the potential for long-term survival (Lee etal., 1997).Similarly, standard chemotherapy o•ers limitede†cacy in the treatment of less common leukemiasand hematologic malignancies. Myelodysplastic syn-drome (MDS) includes a spectrum of bone marrowdisorders characterized by ine•ective hematopoiesisand progression from anemia to eventual leukemictransformation (Heaney and Golde, 1999; Verwilghenand Boogaerts, 1987). Likewise, standard therapy hasachieved only limited success against chronic myelo-monocytic leukemia (CMML) and myeloproliferativedisorders such as polycythemia vera and essentialthrombocythemia (Iland et al., 1995; Najean et al.,1994). While the overproduction of erythrocytes orplatelets can be controlled with marrow suppressivechemotherapy, the underlying disorder is not cured andoften becomes refractory to treatment. Finally, combi-nation chemotherapy has proven to be of little benefitin the treatment of aggressive forms of adult T-cellleukemia (ATL). The clinical course of this hetero-geneous leukemia depends upon the underlying biologyand progression of the individual patient’s disease,rather than upon any therapeutic interventions (Ka-wano et al., 1985). Thus, a therapeutic plateau existsfor standard therapy in many types of leukemias andhematologic malignancies.