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Background: This study was conducted to determine the antineoplastic activities of 5-aza-2′-deoxycytidine (decitabine; DAC) and all-trans retinoic acid (ATRA), administered either alone or in combination, on in vitro cultured SHI-1 cells as well as their effects on the expression of the tumor suppressor gene p16INK4a (p16) and the retinoic acid receptor (RAR)-β. Methods: Cellgrowth inhibition, differentiation and apoptosis were determined in SHI-1 cells treated with DAC and/or ATRA, and the combination index of the two compounds was calculated. Methylation of the p16 and RAR-β genes in SHI-1 cells was detected by methylation-specific polymerase chain reaction (PCR). Real-time quantitative reverse transcriptase PCR was used to detect mRNA expression of the p16 and RAR-β genes, and Western blot analysis was performed for protein expression. Results: The drug combination had a synergistic effect on growth inhibition, differentiation and apoptosis of SHI-1 cells, and the effects of DAC and ATRA weredependent on time. DAC, either alone or in combination with ATRA, induced demethylation of the genes p16 and RAR-β, whereas ATRA alone had no effect on methylation. The RAR-β gene was reexpressed following DAC-ATRA combination treatment, and both agents had no effect on p16 expression. Conclusion: The results revealed that DAC used in combination with ATRA has significant clinical potential in the treatment of acute monocytic leukemia. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The IK6 isoform plays an important role in Philadelphia chromosome-positive adult acute lymphoblastic leukemia (Ph + ALL). This study was designed to monitor the expression of the IK6 isoform with associated cytogenetic and molecular abnormalities. The IK6 isoform, cytogenetic and molecular abnormalities were detected in 100 Chinese patients with de novo Ph+ adult ALL. Expression levels of the IK6 isoform and BCR-ABL1 transcripts were monitored during treatment. BCR-ABL1 mutation was identified in 45 paired samples. Strong correlations were found between the expression status of the IK6 isoform and blast cells, additional cytogenetic abnormalities, BCR-ABL1 transcripts, increased risk of relapse, shorter relapse-free survival and overall survival at diagnosis. Higher frequencies of single IK6 expression and ABL mutation, including the types and shifts thereof, were confirmed in relapsed patients. Furthermore, expression of the IK6 isoform was dynamically consistent with BCR-ABL1 transcript levels during treatment in the single expression group, whereas no such correlation was observed in the co-expression group. The expression pattern of the IK6 isoform was altered in three patients from the co-expression group. The findings of this study in Chinese patients with Ph+ adult ALL exhibit some discrepancies with data reported in other countries, thereby enhancing current knowledge on the therapeutic response and prognosis of this disease. [ABSTRACT FROM AUTHOR]

This study aimed to determine the clinical characteristics and prognostic significance of the meningioma 1 ( MN1) gene and MN1-associated microRNA expression in Chinese adult de novo acute myeloid leukemia (AML) patients. The expression level of MN1, microRNA- 20 ( miR- 20a), and microRNA- 181b ( miR- 181b) in bone marrow mononuclear cells was measured in 158 newly diagnosed AML patients and 20 cases of normal healthy donors by real-time quantitative reverse transcriptase polymerase chain reaction. All AML patients significantly overexpressed MN1 at the level of 0.01983 ( P < 0.001) compared with normal controls. High MN1 expression was associated with spleen involvement ( P = 0.037), NPM1 wild type ( P = 0.001), lower miR- 20a expression levels ( P = 0.015), and higher miR- 181b expression levels ( P = 0.035). MiR- 20a ( P = 0.029) and miR- 181b ( P = 0.017) overexpressed in the bone marrow cells of patients with certain subtypes of AML compared with healthy donors. High MN1 expressers had lower complete remission (CR) rates and shorter overall survival (OS) within the Southwest Oncology Group classification. In multivariable models, high MN1 expression was associated with worse CR rates ( P = 0.01), relapse-free survival (RFS; P = 0.02), and OS ( P = 0.02); high miR- 20a expression was associated with higher CR rates ( P = 0.008) and longer OS ( P = 0.04), whereas high miR- 181b expression was associated with lower CR rates ( P = 0.03), and shorter RFS ( P = 0.045) and OS ( P = 0.017). High MN1 expression confers worse prognosis in Chinese adult patients with de novo AML. MN1 gene and MN1-associated microRNAs provide clinical prognosis of AML patients and may refine their molecular risk classification. [ABSTRACT FROM AUTHOR]

Abstract: Central nervous system (CNS) relapse remains an important cause of morbidity and mortality in acute leukemia, but the mechanisms of CNS infiltration are poorly understood. Some results have shown the blood-brain barrier (BBB) makes CNS become a refugee to leukemic cells and serves as a resource of cells that seed extraneural sites. The authors ask how can leukemic cells disrupt BBB and then successfully enter the CNS in the process of leukemia metastasis. Tight junctions between brain microvessel endothelial cells (BMECs) of BBB possess an intricate complex of transmembrane proteins with cytoplasmic accessory proteins, and hence act as physiological and pharmacological barrier, thereby preventing influx of molecules from the bloodstream into the brain. So the loss of endothelial tight-junction proteins might be an important event related to the disruption of BBB. Vascular endothelial growth factor (VEGF) is one of the potent mediators of vascular permeability and the VEGF secreted by leukemic cells may be implicated in this response. Leukemic cells not only produce VEGF, but also express functional VEGFR, resulting in an autocrine loop for tumor growth and dissemination. It has been observed that forced VEGF over expression triggers proliferation and migration/invasion of some leukemic cells, thereby inducing a more invasive tumor phenotype. It has been identified that VEGF-mediated disruption of endothelial transmembrane tight-junction proteins is contributed to the breakdown of BBB in some CNS inflammation disease. Here, we hypothesize that VEGF secreted by leukemic cells also plays an important role in increasing the permeability of BBB by disrupting endothelial tight-junction proteins and give leukemic cells an entrance to the CNS in CNS leukemia. We propose the key tight-junction proteins claudin-5, occludin, and ZO-1 as targets of VEGF action in promoting BBB breakdown, and in interfering with the VEGF/VEGFR pathway using anti-VEGF or anti-VEGFR antibodies can reduce the permeability of BBB. All these will be tested on the BBB model in vitro and in vivo based on an animal model of CNS leukemia. This hypothesis is useful for exploring the mechanism of leukemic CNS infiltration. If correct, the mechanism put forward here will provide a potent evidence for anti-VEGF strategies in treatment of CNS leukemia. [Copyright &y& Elsevier]

WT1, a tumor suppressor gene responsible for the development of childhood kidney tumors, is now also thought to be involved in the occurrence of human leukemia. First, evidence has shown that WT1 functions during hematopoiesis and regulates the proliferation and differentiation of blood cells. Second, specific expression patterns of this gene correlate with the malignant phenotype of leukemia compared with the physiological situation. Third, mutations of WT1 can be detected, though not frequently, in human leukemia but not in normal hematopoietic cells. Thus, a possible role of WT1 in human leukemogenesis has been proposed. Because the expression of this gene is relatively high during the so-called myelodysplastic stages and in all subtypes of human leukemia compared with normal blood cells, the notion has been raised that WT1 can be used as a "panleukemic marker" for the diagnosis of leukemia at the molecular level. The expression level of WT1 may have significance in predicting prognosis and monitoring relapse. Moreover, with a deeper understanding of its role in leukemogenesis, WT1 may serve as a target molecule in the strategy of gene therapy for leukemia. [ABSTRACT FROM AUTHOR]

Abstract: Real-time quantitative reverse transcriptase polymerase chain reaction method was established for detecting the expression levels of WT1 gene and WT1+17AA isoforms in 226 acute myeloid leukemia (AML) bone marrow (BM) cells. The results showed that WT1 gene was 2–3 logarithms expressed more in AML BM cells at initial diagnosis or relapse than in normal BM cells (p <0.001), with predominant WT1+17AA isoforms expression (the ratio of WT1+17AA/WT1 more than 0.50). Interestingly the ratio of WT1+17AA/WT1 was statistically higher in relapsed AMLs than in initially diagnosed (p =0.01), speculating that WT1+17AA isoforms might participate in AML relapse. [Copyright &y& Elsevier]

Background BCL11A encodes a C2H2 type zinc-finger protein. During normal haematopoietic cell differentiation BCL11A expression is down-regulated. Data in mice suggest up-regulation of BCL11A is involved in the pathogenesis of myeloid leukaemias. BCL11A expression in persons with acute myeloid leukaemia (AML) is not systematically studied. Objective Interrogate associations between BCL11A expression at diagnosis and clinical and laboratory valuables and outcomes in newly-diagnosed persons with AML. Methods We determined BCL11A mRNA levels in bone marrow and blood mononuclear cells in 292 consecutive newly-diagnosed subjects with AML by reverse transcript and real-time polymerase chain reaction. Data were compared to mRNA levels in bone marrow cells of normals. Results Subjects with BCL11A transcript levels at diagnosis exceeding the median value of 2.434 (±3.423 SD; 25th–75th inter-quartile range, 1.33–4.29) had higher WBC levels, a greater proportion of bone marrow myeloblasts, were more likely to be FAB M 0 subtype, less likely to be FAB M 3 subtype, more likely to be in the intermediate cytogenetic risk cohort, less likely to have a complex karyotype and more likely to have DNMT3A R882 and FLT3 -ITD mutations than subjects with transcript levels below the median value. In 89 subjects receiving conventional induction chemotherapy the complete remission rate was 54% (95% confidence interval [CI]; 33, 75%) in the lower BCL11A cohort and 65% (45, 85%; P = 0.26) in the higher BCL11A cohort. 3 year survival was 33% (2, 65%) in the lower BCL11A cohort and 15% (0, 39%; P = 0.35) in the high BCL11A cohort. Conclusion BCL11A transcript levels at diagnosis was significantly associated with several clinical and laboratory variables. There were also non-significant associations with complete remission rate and survival. These data suggest a possible role for BCL11A expression in AML biology. [ABSTRACT FROM AUTHOR]

Abstract: TNFR-associated factors (TRAFs) participate in diverse biological processes, such as adaptive and innate immunity, stress response, and bone metabolism. We report that all TRAFs except TRAF3 are expressed at mRNA and protein levels in B cell-derived Hodgkin''s lymphoma cell lines (L428 and KM-H2). Both the classical (p50–RelA) and the alternative NF-κB activity (p52–RelB) are sustained in L428 and KM-H2 cells. A successful depletion of TRAF1 protein expression by means of RNA interference abrogates the anti-apoptosis activity in L428 cells. The TRAF1-deficiency reduces the classical NF-κB activity but not the alternative activity. The expression of the NF-κB targeting genes, such as ICAM-1, c-Flip, and Cyclin D1, is suppressed in the TRAF1-depleted cells. On the other hand, CD30 signaling upregulates the TRAF1 expression while reducing the expression of TRAF2 and TRAF5. Importantly, the CD30-induced alternative NF-κB activation is inhibited by the depletion of the TRAF1 expression. We also demonstrate that the phosphorylation of the extracellular signal-regulated kinase (ERK) upon CD30 stimulation in Hodgkin''s lymphoma cells is independent of TRAF1 expression. Our data shed new light on the function of TRAF1 in B cell-derived lymphoma cells. We conclude that TRAF1 is an important molecule mediating both the CD30 signaling-dependent and independent NF-κB activation, which prevents the lymphoma cells from spontaneous and induced apoptosis. [Copyright &y& Elsevier]