Magnesium contents of leukemic lymphocytes

In this study, magnesium concentrations were measured in lymphocytes from patients with acute myeloblastic leukemia (AML), chronic megalositer leukemia (KML) and acute lymphoblastic leukemia (ALL) before and after chemotherapy management, and results were compared with those of control subjects. Magnesium concentrations were higher in the patient groups compared with control values. However, no meaningful differences were found among magnesium concentrations of the patient groups themselves. Similarly, no statistically meaningful differences were found between lymphocyte magnesium concentrations before and after chemotherapy management in the patient groups. In the inter-correlation analysis, we observed no correlations between pre- and post-magnesium concentrations in patients' lymphocytes. It has been suggested that magnesium concentrations of leukemic lymphocytes might increase due to the high ATP requirement of the leukemic cells since magnesium is known to play an important part as a cofactor in most of the energy-producing reactions.     

Low IL-23 levels in peripheral blood and bone marrow at diagnosis of acute leukemia in children increased with the elimination of leukemic burden

IL-23 is an IL-12 cytokine family member with pleiotropic functions that regulates tumour growth in various cancer types, exhibiting both anti-tumorigenic and pro-tumorigenic properties. Preclinical studies have shown a potential anti-leukemic action on childhood B-ALL cells. The study involved 65 children with acute leukemia [59 patients with acute lymphoblastic leukemia (ALL) and 6 patients with acute myeloid leukemia (AML)] and 27 healthy controls. Using an enzyme-linked immunosorbent assay, we aimed to determine the IL-23 levels in the peripheral blood (PB) and bone marrow (BM) of patients at diagnosis and at the end of the induction therapy (EIT). PB IL-23 levels were lower in leukemia patients compared to the healthy controls. In all acute leukemia patients, IL-23 levels were significantly lower at diagnosis both in PB (P = .015) and in BM (P = .037) compared to the PB and BM concentrations at the EIT. The same pattern was present in both subgroups of ALL and AML patients. The high leukemic burden at diagnosis was related with lower IL-23 levels, which were increased with the disease remission. Considering the anti-leukemic potential of this cytokine, the elevation of the IL-23 concentration at the disease remission indicates a beneficial role of IL-23 in paediatric acute leukemia.     

Distribution of the cytoskeletal protein,Nestin, in acute leukemia

Abstract

Nestin is a neuroepithelial stem cell marker that is expressed in some types of tumor cells. Recent reports suggest that Nestin may be closely related to malignant cell proliferation and migration. Acute leukemia (AL) is characterized by a lack of differentiation, which results in uncontrolled proliferation in the bone marrow and accumulation of immature cells. The expression and function of Nestin in AL is unclear. We investigated Nestin immunohistochemical patterns of 87 patients that included 47 cases of acute myeloid leukemia (AML) and 40 cases of acute lymphoblastic leukemia (ALL), and 20 patients in complete remission (CR) from AML or ALL. We also investigated the clinico-pathological features of 87 cases of AL and their CR and overall survival (OS). Nestin was expressed in leukemic blasts and mature granulocytic cells in most cases (39/47) of AML. Conversely, Nestin was expressed in mature granulocytic cells in fewer cases (6/40) of ALL, but not in blasts. Nestin expression appeared in leukemic blasts of AML, but not ALL. Nestin expression in AML blast cells was not associated with CR or OS. We provide evidence that Nestin is expressed in AL and might be a useful immunohistochemical marker for identifying AML and ALL.     

Derepression of the Iroquois Homeodomain Transcription Factor Gene IRX3 Confers Differentiation Block in Acute Leukemia

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异基因造血干细胞移植后并发自身免疫性溶血性贫血的治疗进展

异基因造血干细胞移植（HSCT）后自身免疫性溶血性贫血（AIHA）是HSCT后并不少见的并发症,其发病率约1﹪~ 6﹪,不同于一般的AIHA,HSCT后AIHA发病机制尚未完全明确,可能与HSCT后受者体内免疫失调相关。危险因素与移植患者年龄小、非恶性疾病、使用无关供者、半相合供者移植、脐血移植、去T细胞移植及移植后并发慢性移植物抗宿主病（GVHD）等有关。皮质激素作为一线治疗,疗效有限,难以持续缓解,需联合使用利妥昔单抗（RTX）、大剂量丙种球蛋白等,甚至需要联合霉酚酸酯、环磷酰胺、西罗莫司、阿伦单抗、依库丽单抗或蛋白酶体抑制剂硼替佐米等免疫抑制剂治疗,部分患者需行血浆置换,偶有行脾切除术者。移植后AIHA总死亡率常高达50﹪,总体预后差于单纯AIHA。该综述旨在总结HSCT后并发AIHA的最新治疗进展,供临床医师参考。     

A distinct beta-hexosaminidase isoenzyme separated from human leukemic lymphocytes and myelocytes

The beta-hexosaminidase (EC 3.2.1.30) isoenzymes were separated on the basis of their carbohydrate moieties by an affinity chromatography using immobilized phenylboronate. Normal lymphocytes and granulocytes contain two major forms of beta-hexosaminidase, acute lymphoblastic, acute myeloblastic, chronic lymphocytic and chronic myelocytic leukemic cells contain an extra, distinct isoenzyme of beta-hexosaminidase. This extra isoenzyme may be a marker for the leukemic conversion of hematopoietic tissue.     

急性髓性白血病HB-1细胞系细胞具有侵入CBA/N小鼠脑部的能力

急性髓性白血病HB-1细胞系是由辐射处理的CBA／N小鼠脾脏细胞克隆并建立起来的。静脉注射HB-1细胞到正常CBA／N小鼠体内会诱发急性髓性白血病综合症,并使小鼠2周左右死亡。一般情况下,白血病细胞被接种到小鼠后会侵入造血器官、肺、肾和肝脏。我们在研究中发现了一令人感兴趣的现象,不仅在小鼠的肺、肾和肝脏中,而且在大脑和小脑中也观察到了HB-1细胞。白血病细胞能穿过血脑屏障在正常情况下是难以理解的,因为血脑屏障可阻止血细胞进入脑内,并且严格有选择地让小分子通过。因此,HB-1细胞将是阐明形成血脑屏障的内皮细胞上的附贴分子和选择性地让特殊细胞侵入脑的一个很好的模型。     

Interleukin-17 in acute myeloid leukemia

There are several reports that angiogenesis plays important roles in hematological malignancies including acute myeloid leukemia (AML). Human interleukin-17 (IL-17) is a proinflammatory cytokine produced by activated CD4 T cells. IL-17 plays a potential role in T cell mediated angiogenesis. The role of IL-17 in pathologic angiogenesis has not been evaluated yet. The aim of the study was to determine plasma level of IL-17 in patients with AML. IL-17 levels were measured by ELISA in plasma samples taken from 68 adult patients with AML before chemotherapy was administered. In addition 20 out of 68 patients were reanalysed after achieving complete remission (CR). Ten samples from healthy volunteers were evaluated as the control. In this study we have demonstrated that serum level of IL-17 is not elevated in AML patients. These results suggest that angiogenesis in AML is not mediated by CD4 T cells. To our knowledge this is the first report about IL-17 serum level in acute leukemias. We are currently evaluating IL-17 levels in others haematological malignancies.     

Effect of iron supplementation on oxidative stress and antioxidant status in iron-deficiency anemia

This study was designed to measure the effect of iron supplementation on antioxidant status in iron-deficient anemia, including the time for hemoglobin normalization and at the time of filling of iron body stores. The extent of plasma lipid peroxidation was evaluated by measuring the levels of malondialdehyde and glutathione peroxidase (GSH-Px), and the activities of superoxide dismutase (SOD) and catalase in 63 patients with iron-deficiency anemia before and after 6 wk of iron supplementation and at the time when body iron stores are saturated. After 6 wk of iron supplementation, a significant decrease of oxidative stress was observed in the treated subjects relative to controls (p<0.05). No significant differences existed between treated patients at 6 wk and at the end of the study. The erythrocyte levels of catalase, SOD, and GSH-Px were significantly lower in treated patients relative to controls (p<0.05). These levels increased after 6 wk of supplementation (p<0.05) and showed no significant differences with those at the end of the study.     

Microtubules play an essential role in the survival of primary acute lymphoblastic leukemia cells advancing through G1 phase

We recently reported that primary acute lymphoblastic leukemia (ALL) cells are susceptible to the microtubule depolymerizing agent vincristine (VCR) in G1 phase. This finding prompted testing another G1 phase-active compound, palbociclib (PCB), a highly selective inhibitor of cyclin-dependent kinases 4/6 (CDK4/6), alone and in combination with VCR. PCB used alone caused G1 arrest in ALL cells with no effect on cell viability, and similar results were obtained for the retinoblastoma (RB)-proficient T98G glioblastoma cell line. In contrast, HeLa cells failed to arrest in the presence of PCB, consistent with their lack of dependence on the CDK4/6-RB pathway. When ALL cells were pretreated with PCB, they became refractory to death in G1 phase induced by VCR treatment, whereas HeLa cells retained VCR sensitivity after PCB pretreatment. Immunofluorescence microscopy showed that PCB did not disrupt the microtubule network nor prevent VCR from doing so. Furthermore, ALL cells pretreated with PCB retained susceptibility to the Bcl-2/Bcl-xL inhibitor ABT-263, indicating that downstream apoptotic signaling was unaffected. When released from PCB-enforced arrest, ALL cells reinitiated cycling and regained sensitivity to VCR. ALL cells treated with cycloheximide also arrested in G1 phase and became insensitive to VCR, independently reinforcing conclusions derived from PCB-imposed arrest. Thus, primary ALL cells advancing through G1 phase are strictly dependent on functional microtubules for survival whereas microtubules are dispensable for G1-arrested cells. These findings provide novel insight into interphase microtubule function and, from a therapy standpoint, strongly caution against combining microtubule targeting agents and CDK4/6 inhibitors for ALL.     

The inhibitor of apoptosis protein family and its antagonists in acute leukemias

The Inhibitor of Apoptosis Protein family (IAP) functions as inhibitors of apoptotic pathways, both death receptor- and mitochondrial mediated. We detail the current body of knowledge for the IAP family with regard to their structure and function, their expression in normal and leukemic cells, and their prognostic importance in acute leukemia. Although there is some evidence that IAPs play an important role in the chemoresistance of leukemia cell lines, little is known about their influence on this phenomenon in acute leukemia cells of human origin. IAPs are also explored as a specific target for new antitumor strategies, including antisense oligonucleotides of XIAP (X-chromosome-linked IAP) or survivin and small molecules of polyphenylurea-based XIAP inhibitors. Several proteins negatively regulate the function of the IAP family. One of those antagonists is Smac/DIABLO. Short peptides of Smac were found to enhanced apoptosis, induced by chemo- or immunotherapy, in the leukemic cells in vitro. Moreover, small-molecule agents, resembling Smac/DIABLO in function, were shown to potentiate cytotoxicity of chemotherapy in different malignancies. IAPs, exhibiting downstream influence on both external and intrinsic pathways as well as on some caspase-independent mechanisms of apoptosis, are potentially attractive target for anti-tumor therapy, although their role in the pathology and prognosis of acute leukemia has to be further elucidated.     

Butyrate regulates the expression of inflammatory and chemotactic cytokines in human acute leukemic cells during apoptosis

Butyrate is a histone deacetylase inhibitor implicated in many studies as a potential therapy for various forms of cancer. High concentrations of butyrate (>1.5 mM) have been shown to activate apoptosis in several cancer cell lines including prostate, breast, and leukemia. Butyrate is also known to influence multiple signaling pathways that are mediators of cytokine production. The purpose of this study was to evaluate the impact of high concentrations of butyrate on the cancer microenvironment vis-à-vis apoptosis, cellular migration, and capacity to modulate cytokine expression in cancer cells. The results indicate that high concentrations of butyrate induced a 2-fold activation of caspase-3 and reduced cell viability by 60% in U937 leukemia cells. Within 24 h, butyrate significantly decreased the levels of chemokines CCL2 and CCL5 in HL-60 and U937 cells, and decreased CCL5 in THP-1 leukemia cells. Differential effects were observed in treatments with valproic acid for CCL2 and CCL5 indicating butyrate-specificity. Many of the biological effects examined in this study are linked to activation of the AKT and MAPK signaling pathways; therefore, we investigated whether butyrate alters the levels of phosphorylated forms of these signaling proteins and how it correlated with the expression of chemokines. The results show that butyrate may partially regulate CCL5 production via p38 MAPK. The decrease in p-ERK1/2 and p-AKT levels correlated with the decrease in CCL2 production. These data suggest that while promoting apoptosis, butyrate has the potential to influence the cancer microenvironment by inducing differential expression of cytokines.     

Argonaute 2 sustains the gene expression program driving human monocytic differentiation of acute myeloid leukemia cells

MicroRNAs are key regulators of many biological processes, including cell differentiation. These small RNAs exert their function assembled in the RNA-induced silencing complexes (RISCs), where members of Argonaute (Ago) family of proteins provide a unique platform for target recognition and gene silencing. Here, by using myeloid cell lines and primary blasts, we show that Ago2 has a key role in human monocytic cell fate determination and in LPS-induced inflammatory response of 1,25-dihydroxyvitamin D₃ (D3)-treated myeloid cells. The silencing of Ago2 impairs the D3-dependent miR-17-5p/20a/106a, miR-125b and miR-155 downregulation, the accumulation of their translational targets AML1, VDR and C/EBPβ and monocytic cell differentiation. Moreover, we show that Ago2 is recruited on miR-155 host gene promoter and on the upstream region of an overlapping antisense lncRNA, determining their epigenetic silencing, and miR-155 downregulation. These findings highlight Ago2 as a new factor in myeloid cell fate determination in acute myeloid leukemia cells.