We retrospectively investigated the prognostic factors of acute myeloid leukemia (AML) in 152 Chinese patients with de novo AML who were older than 60 years of age and who received treatment at our hospital. Log-rank test showed that 6 parameters including older age, higher white blood cell (WBC) counts, lactate dehydrogenase (LDH) and bone marrow (BM) blasts at diagnosis, unfavorable risk cytogenetics, and non-mutated CEBP? were significant adverse prognostic factors of overall survival (OS) for elderly AML patients (P ?=? 0.0013, 0.0358, 0.0132, 0.0242, 0.0236 and 0.0130, respectively). Moreover, older age and higher LDH were significant adverse predictors for relapse-free survival (RFS) (P ?=? 0.0447 and 0.0470, respectively). Univariate analysis revealed similar results for OS to those of the log-rank test and only higher LDH at diagnosis was a significant adverse predictor for RFS (P ?=? 0.028, HR: 1.979, 95%CI: 1.075-3.644). In multivariate analysis, we identified 2 trends towards independent prognostic factors for OS, including BM blasts at diagnosis (P ?=? 0.057, HR: 1.676, 95%CI: 0.984-2.854) and mutation status of CEBP? (P ?=? 0.064, HR: 4.173, 95%CI: 0.918-18.966). Our data indicated that older age, gender and a previous history of hematologic diseases resulted in lower complete remission rate (P ?=? 0.012, 0.051 and 0.086, respectively). We further developed an easy scoring system for predicting prognosis and response to induction therapy in older AML patients. Patients who had lower scores showed significantly longer OS and RFS (P ?=? 0.0006 and 0.1001, respectively) and higher CR rate (P ?=? 0.014). Our research is limited by its retrospective nature and the results from our study need to be further validated by prospective randomized clinical trials.
Loss of cylindromatosis gene (CYLD) expression has been observed in various cancers, including chronic lymphocytic leukemia (CLL). As a deubiquitination enzyme, CYLD regulates the proliferation, development and activation of lymphoid cells. Here we determined the CYLD mRNA expression by quantitative polymerase chain reaction (PCR) in 125 patients with CLL. CYLD was considerably down-regulated in CLL cells compared to normal B cells. Low CYLD expression was associated with unmutated status of the immunoglobulin heavy-chain variable-region (IGHV) gene (p = 0.0018) and CD38 positivity (p = 0.0499). Patients with high CYLD expression showed a trend toward improved overall survival (OS) (10-year OS: CYLD high: 94.74%, CYLD low: 52.71%; p = 0.0534). For patients with mutated IGHV gene, high CYLD was also associated with better OS (10-year OS: CYLD high: 100%, CYLD low: 66.67%; p = 0.0547). In conclusion, low CYLD expression identifies a subgroup of patients with CLL with inferior outcome, indicating the role of CYLD as a tumor suppressor in the pathogenesis of CLL.
Lymphoid enhancer-binding factor 1 (LEF1) is a downstream effector of the Wnt/?-catenin signaling pathway and its dysregulation is associated with a number of malignant diseases such as leukemia. We explored the expression profile of LEF1 in acute myeloid leukemia (AML) and determined its specific prognostic significance in this disease. The LEF1 mRNA level in patients with previously untreated AML was significantly higher than in normal controls. Patients with AML with relatively higher LEF1 expression were more likely to achieve a complete remission (CR) following induction therapy in comparison to those with a lower LEF1 level. Moreover, we provide the first evidence that primary AML samples with AML1-ETO or PML-RAR? have a higher LEF1 level compared with those without each fusion gene. High LEF1 expression predicts a significantly better overall survival for patients with intermediate-risk cytogenetics. High LEF1 level was associated with a favorable relapse-free survival in patients with FLT3-ITD wild-type. Finally, a scoring system based on LEF1 level and mutation status of FLT3-ITD or NPM1 is reliable to predict the outcome for AML with intermediate-risk cytogenetics. Our results indicate that LEF1 contributes to the pathophysiology of AML and could serve as a novel predictor of better treatment response. LEF1 level may be incorporated into an improved risk classification system for certain specific subtypes of AML.
Bcl-2-associated athanogene 3 (BAG3), a member of BAG family, is shown to sustain cell survival and underlie resistance to chemotherapy in human neoplastic cells. We aimed to determine the exact role and underlying mechanisms of BAG3 in human chronic lymphocytic leukemia (CLL). One hundred human CLL samples and 20 normal B-cell samples from healthy controls were collected. We measured the BAG3 expression in these cells and explored its relationship with known prognostic factors for CLL. The roles of BAG3 in cell apoptosis and migration were evaluated by small interfering RNA-mediated knockdown of BAG3 in primary CLL cells. We showed that BAG3 expression level was increased in CLL cells compared with normal B cells. Moreover, BAG3 expression was particularly upregulated in CD38 positive, unmutated immunoglobulin heavy-chain patients and those with lymphadenopathy and/or splenomegaly. Importantly, patients with increased BAG3 expression level have poor overall survival in subgroups with positive ZAP-70 or those without any "p53 abnormality". In addition, knocking down of BAG3 expression resulted in increased apoptotic ratio and decreased migration in primary CLL cells. Our data indicate that BAG3 is a marker of poor prognostic in specific subgroups of CLL patients and may be a potential therapeutic target for this disease.
The corticotropin-releasing factor (CRF) family of neuropeptides is composed of CRF, urocortin 1 (UCN 1), UCN 2 and UCN 3, which can bind to CRF-binding protein (CRF-BP) and two known receptors, CRFR1 and CRFR2, to perform many pathophysiological functions, including inflammation. In contrast to its anti-inflammatory effect in the central nervous system, the roles of the CRF family and its receptors in the periphery are diverse. However, the biological activities of the CRF family in inflammation are circumstantial and remain controversial. It is suggested that this diverse effects of the CRF family may be due to the different types of CRF receptors, different cells and tissues and even different concentrations of CRF family peptides. Though there are difficulties or limitations in establishing the exact modulatory roles of the CRF family and its receptors in peripheral inflammation, the application of CRF receptor agonists or antagonists to treat inflammatory diseases is being pursued with increasing interest. This review describes the effects and mechanisms of the CRF family and its receptors in inflammation; the possible application of CRF receptor agonists or antagonists in inflammatory diseases or disorders will also be discussed.
Bcl-2-associated athanogene (BAG) family proteins share the BAG domain, which is characterized by their interaction with a variety of partners (heat shock proteins, steroid hormone receptors, Raf-1 and others) and is involved in regulating a number of cellular processes. BAG3, also known as CAIR-1 or Bis, mediates protein delivery to proteasome and modulates apoptosis by interfering with cytochrome c release, apoptosome assembly and other events in the cellular death program. Moreover, it takes part in the processes of cell adhesion and migration. It has been shown that, in human cancer cells, including lymphocytic and myeloblastic leukemic cells, BAG3 sustains cell survival and underlies resistance to chemotherapy, through down-modulation of apoptosis. BAG3 knocking down could enhance the effectiveness of chemotherapy. This review summarizes the physiological and pathological roles of BAG3 in cancer cells and its potential as a therapeutic target of human malignancies.
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