IntroductionSignal transducer and activator of transcription (STAT) proteins are a family of latent cytoplasmic transcription factors involved in cytokine, hormone, and growth factor signal transduction. 1-7 STAT proteins mediate broadly diverse biologic processes, including cell growth, differentiation, apoptosis, fetal development, transformation, inflammation, and immune response. The intent of this review is to provide a brief synopsis of the role of STAT activation in signal transduction, the structure of STAT proteins, mechanisms of aberrant signal transduction, and the role of STAT proteins in normal and malignant hematopoiesis. The review focuses in particular on the role of STAT activation in leukemogenesis. STATs in signal transductionThe interaction of a cytokine with its ligand-binding receptor ␣ subunit is the first step in the formation of a signaling-competent receptor complex. This process involves the oligomerization of the ligand-bound subunit with either another subunit or a separate, signal-transducing ␤ subunit. 8,9 This oligomerization initiates the process of signal transduction by activation of the receptorassociated Janus family tyrosine kinases (JAKs) through crossphosphorylation ( Figure 1). Immediate targets of the activated JAKs are the cytoplasmic portions of the receptors and receptorassociated proteins. The tyrosine phosphorylated sites become docking elements for Src homology 2 (SH2)-and phosphotyrosylbinding domain-containing proteins present in the membrane or the cytoplasmic compartment. Prominent among these are the STATs. Receptor-recruited STATs are phosphorylated on a single tyrosine residue in the carboxy terminal portion. The modified STATs are released from the cytoplasmic region of the receptor subunits to form homodimers or heterodimers through reciprocal interaction between the phosphotyrosine of one STAT and the SH2 domain of another. Following dimerization, STATs rapidly translocate to the nucleus and interact with specific regulatory elements to induce target gene transcription. STAT family members and chromosomal localizationSTAT proteins were originally discovered in interferon (IFN)-regulated gene transcription in the early 1990s. [10][11][12] Since then, a number of cytokines have been recognized to activate various STAT proteins (Table 1). Seven members of the STAT family of transcription factors have been identified in mammalian cells: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.Convincing evidence from genetic mapping studies indicates a common ancestral origin that gave rise to 3 chromosomal clusters of STAT genes through a series of duplication processes (Table 2). 37 Structure of STATsPrevious characterization of the crystal structure of STAT molecules allowed a better understanding of the distinct functional domains within the STAT proteins. 38,39 Several domains are conserved in all STAT family members ( Figure 2; Table 3). STAT isoformsSTAT isoforms lacking regions of the c-terminal domain have a competitive dominant-negative (DN) effect on...

Signal transducer and activator of transcription (STAT) proteins are involved in hematopoietic cytokine receptor signaling pathways that regulate cell proliferation, differentiation, and survival. STATs are dysregulated in acute myeloid leukemia (AML); mechanisms of dysregulation include constitutive activation and truncation of the C-terminal transactivation domain; the latter results in a ␤ isoform that has a trans-dominant negative effect on gene induction mediated by the fulllength STAT␣ form. It was hypothesized that constitutive STAT activity might correlate with unfavorable treatment outcome in AML. Pretreatment bone marrow samples from 63 adult patients with AML were analyzed by electrophoretic mobility shift assay for the presence of STAT DNA-binding activity. Isoforms and relative levels of STAT proteins were determined by immunoblotting. Constitutive STAT3 activity was detected in samples from 28 (44%) patients. Pretreatment clinical characteristics, expression of STAT␣/␤ isoforms, and treatment regimens did not differ significantly between patients with and without constitutive STAT3 activity. Disease-free survival (DFS) was significantly shorter in patients with than in patients without constitutive STAT3 activity (median 8.7 vs 20.6 months; P ‫؍‬ .01).Overall survival did not differ significantly. The subgroup of patients with constitutive STAT3 activity and the STAT3␤ isoform had the shortest DFS (P ‫؍‬ .006) and shorter overall survival (P ‫؍‬ .049) than all other patients. Whether adverse treatment outcome is attributable to constitutive STAT activity itself or to a process that leads to constitutive STAT activity remains to be determined. This is the first demonstration of a prognostic significance for STAT proteins in a malignancy. (Blood. 2002;99:252-257)

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BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are a biologically heterogeneous group in which various gene alterations have been reported. The aim of this study was to investigate the frequency and prognostic impact of BCL2, BCL6, and MYC rearrangements in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP)-treated DLBCL cases. METHODS: Tissue microarrays were constructed from 239 cases of DLBCL, and the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by immunohistochemistry. MYC, BCL2, and BCL6 rearrangements were investigated by interphase fluorescence in situ hybridization on tissue microarrays. Survival analysis was constructed from 145 R-CHOP-treated patients. RESULTS: MYC, BCL2, and BCL6 rearrangements were detected in 14 (6%), 36 (15%), and 69 (29%) of 239 DLBCL patients. Double or triple rearrangements were detected in 7 (3%) of 239 DLBCL cases. Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and 1 had BCL2, BCL6, and MYC rearrangements. The prognosis of these cases was extremely poor, with a median survival of 9 months. MYC rearrangement was associated with significantly worse overall survival (P ¼ .01), especially for the cases with GC phenotype (P ¼ .009). BCL6 rearrangement also predicted significantly shorter overall survival (P ¼ .04), especially for the non-GC phenotype (P ¼ .03). BCL2 rearrangement had no prognostic impact on outcome. International Prognostic Index (P ¼ .004) and MYC rearrangement (P ¼ .009) were independent poor prognostic factors. CONCLUSIONS: Analysis of MYC gene rearrangement along with BCL2 and BCL6 is critical in identifying high-risk patients with poor prognosis. Cancer 2012;118:4173-83.

Signal transducer and activator of transcription (STAT) proteins comprise a seven-member family of latent cytoplasmic transcription factors that are activated through tyrosine phosphorylation by a variety of cytokines and growth factors. Aberrant activation of STATs accompanies malignant cellular transformation with resultant leukemogenesis. Constitutive activation of STATs has been demonstrated in various leukemias. A better understanding of the mechanisms of dysregulation of the STAT pathway and understanding of the cause and effect relationship in leukemogenesis may serve as a basis for designing novel therapeutic strategies directed against STATs. Mechanisms of STAT activation, the potential role of STAT signaling in leukemogenesis, and recent advances in drug discovery targeting the STAT pathway are the focus of this review.

Summary:Adverse reactions with DMSO-cryopreserved stem cell infusion are well-recognized. However, severe, lifethreatening anaphylactic reactions with DMSO are very rarely described in the literature. We report here a 58-year-old female with AL amyloidosis who developed an unexpected episode of respiratory arrest a few seconds after the beginning of thawed stem cell product infusion. Fortunately, the patient was resuscitated successfully without the need for intubation. The prompt development of the reaction just a few seconds after the stem cell infusion convincingly implicates DMSO as the potential suspect. The presence of amyloid cardiomyopathy might have also contributed to this adverse event. Bone Marrow Transplantation (2000) 25, 1299-1301. Keywords: DMSO; respiratory depression; stem cell transplantation; amyloidosis Amyloid light-chain (AL) amyloidosis is now recognized as a plasma cell dyscrasia resulting from the synthesis and deposition of insoluble immunoglobulin light chains in various organ systems.1 Heart involvement has been associated with increased mortality and poorer prognosis.1,2 The conventional alkylating agent-based therapy of AL amyloidosis has been generally unsuccessful with an average overall survival of 12-20 months, and 6 months in patients with cardiac involvement.1 Dose-intensive melphalan with autologous peripheral blood stem cell rescue (APBSCT) has been recently demonstrated to be an effective treatment modality, 3-6 although follow-up is still short-term. 3 However, the early mortality within the first 100 days can be high (up to an average of 30%) mostly due to heart failure associated with amyloid cardiomyopathy. 4,5 Dimethylsulphoxide (DMSO) prevents damage to hemopoietic stem cells during cryopreservation.7 DMSO-cryopreserved autologous stem cell infusions have been reported to cause a wide variety of toxicities which have been mostly mild. tion is very rare and has been reported only in isolated cases. 10-14We present here a patient with AL amyloidosis and cardiac involvement who developed acute respiratory arrest which was reversed successfully with prompt intervention. Case reportA 58-year-old woman presented to another center with bilateral lower extremity edema and fatigue. She was found to have hypoalbuminemia and a nephrotic range proteinuria. A computerized tomography of the abdomen showed a diffusely enlarged liver and bilaterally enlarged kidneys. An electrocardiogram (EKG) revealed first degree AV block and low voltaged QRS waves in leads II, III and aVF and ST segment elevation in V 1 and V 2 and T inversion in V 3 to V 6 . An echocardiogram was obtained which showed mild left ventricular hypertrophy with a normal ejection fraction of 55%. The patient subsequently underwent a kidney biopsy which revealed sclerosis and obsolescence of several glomeruli with accumulation of Congo-red positive eosinophilic material within the mesangium and the glomerular capillary walls. Lambda light chains were stained only in the glomeruli and blood vessels by immunofluorescence...

There is a subclinical decrease in right ventricular systolic and diastolic echocardiographic indices, although mostly, in the normal range, in a relatively short time interval after onset of chemotherapy.

Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia, Philadelphia-positive acute lymphoblastic leukemia, and advanced gastrointestinal stromal tumors. Several cases of hepatotoxicity, including fatal liver failure, have been reported with the long-term use of imatinib mesylate. Generally hepatotoxicity resolves after discontinuation of imatinib. Despite discontinuation of imatinib, hepatotoxicity can be progressive. Steroid may be useful in these patients and should be started early. We report a 53-year-old woman with advanced gastrointestinal stromal tumors who developed hepatotoxicity while receiving imatinib and subsequently acute liver failure. Ten weeks after commencing imatinib treatment, hepatotoxicity was determined. Imatinib was immediately ceased. Subsequently, a week later hepatic encephalopathy, jaundice, and coagulopathy occurred. Prednisolone was commenced. Liver biopsy was performed five weeks after the determining of hepatotoxicity. Biopsy showed sinusoidal congestion, necrosis of hepatocytes, inflammation, and hepatocyte drop out around the hepatic venule consistent with drug toxicity. Her liver function tests normalized with a nine-week prednisolone treatment. The patient was discharged. Her liver enzymes remained in normal range following visits. In cases of imatinib-induced acute hepatitis, the administration of prednisolone may be useful in the resolution of the acute episode and allow the reintroduction of a drug without risking recurrence of hepatitis.