Fibrinogen--proteolysis in acute myelogenous leukemia (AML)

Fibrinopeptides were measured as direct indices of thrombin, plasmin and elastase in plasma samples obtained from patients with AML. Peptide patterns observed were consistent with spontaneous or drug induced plasmin-specific fibrinogenolysis (AML FAB M 1/3), elastase mediated proteolysis (AML FAB M 3/4) or DIC (AML FAB 4/5). DIC was also observed in septic, agranulocytotic patients.     

Cytomorphological and cytochemical classification of acute myeloid leukaemia (AML)

One hundred cases of adult AML were classified cytomorphologically (FAB-classification) and cytochemically (Loeffler's classification). From this combined analysis it could be shown that some corrections have to be made in the FAB-classification; particularly groups M-1 and M-4 had to be reclassified. The authors, therefore, advocate that the final FAB-classification should be the result of cytomorphologic as well as cytochemical analysis.     

Acute Myeloid Leukemia (AML) with Erythroid Predominance Exhibits Clinical and Molecular Characteristics that Differ from Other Types of AML

The clinical importance of erythroid predominance in bone marrow of patients with acute myeloid leukemia (AML) is controversial. These cases represent a heterogeneous group of diseases that historically have been classified into different categories. We studied 313 AML patients and specifically compared the clinical, cytogenetic, and molecular features of cases of AML with erythroid predominance, arbitrarily defined as ≥50% erythroid precursors, to AML cases without erythroid predominance. We also assessed 51 patients with a high-grade myelodysplastic syndrome (MDS), refractory anemia with excess blasts (RAEB). All neoplasms were classified according to the World Health Organization classification. With the exception of therapy-related AML/MDS, the presence of erythroid predominance in variously classified categories of AML was associated with a survival advantage. In addition, AML with erythroid predominance had a lower frequency of cytogenetic abnormalities as well as a lower frequency of mutations involving NPM1, NRAS and FLT3 as compared with AML without erythroid predominance. We conclude that the clinical, cytogenetic, and molecular features of AML with erythroid predominance in the non-therapy-related setting are much closer to those of a high-grade myelodysplastic syndrome than they are to other types of AML.     

Low-dose cytosine-arabinoside in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

Ten AML- and two MDS-patients in whom conventional chemotherapy was contraindicated or ineffective were treated with low dose ARA-C, 10 mg/m2 per 12hS.C. for 2-4 weeks. Seven patients obtained a complete and two a partial remission. Our findings suggest that low dose ARA-C may act both by induction of differentiation and/or inhibition of proliferation.     

T lymphocyte chemotactic chemokines in acute myelogenous leukemia (AML): local release by native human AML blasts and systemic levels of CXCL10 (IP-10), CCL5 (RANTES) and CCL17 (TARC)

T cell targeting immunotherapy is now considered in acute myelogenous leukemia (AML), and local recruitment of antileukemic T cells to the AML microcompartment will then be essential. This process is probably influenced by both intravascular as well as extravascular levels of T cell chemotactic chemokines. We observed that native human AML cells usually showed constitutive secretion of the chemotactic chemokines CXCL10 and CCL5, whereas CCL17 was only released for a subset of patients and at relatively low levels. Coculture of AML cells with nonleukemic stromal cells (i.e., fibroblasts, osteoblasts) increased CXCL10 and CCL17 levels whereas CCL5 levels were not altered. However, a wide variation between patients in both CXCL10 and CCL5 levels persisted even in the presence of the stromal cells. Neutralization of CXCL10 and CCL5 inhibited T cell migration in the presence of native human AML cells. Furthermore, serum CCL17 and CXCL10 levels varied between AML patients and were determined by disease status (both chemokines) as well as patient age, chemotherapy and complicating infections (only CCL17). Thus, extravascular as well as intravascular levels of T cell chemotactic chemokines show a considerable variation between patients that may be important for T cell recruitment and the effects of antileukemic T cell reactivity in local AML compartments.     

Astragalus membranaceus lectin (AML) induces caspase-dependent apoptosis in human leukemia cells

Objectives: Recently, plant lectins have attracted great interest due to their various biological activities such as anti‐cancer, anti‐fungal and anti‐viral activities. We have reported earlier concerning anti‐proliferation of human cancer cell lines by a galactose‐binding lectin (AML), from a Chinese herb, Astragalus membranaceus. In the present study, detailed investigations into the mechanism of such anti‐proliferation properties have been carried out. Materials and methods: Mechanism of apoptosis initiation in K562 cells by AML was investigated by morphology, flow cytometry and western blot analysis. Results: AML induced apoptosis in a caspase‐dependent manner in the chronic myeloid leukemia cell line, K562. Furthermore, we observed that cytotoxicity and apoptosis of K562 cells induced by AML were completely abolished in presence of lactose or galactose. Conclusions: Our results suggest that AML could act as a potential anti‐cancer drug.     

RNA splicing and SR protein phosphorylation under stress in acute myeloid leukemia (AML)

SR proteins are essential splicing factors required for constitutive splicing and serving as key regulators of alternative RNA splicing. SR proteins purified from late vaccinia virus infected cells (SR-VV) are hypo-phosphorylated and functionally inactivated as splicing regulatory proteins by a virus-induced partial dephosphorylation, similar to that seen late during an adenovirus infection [Kanopka et al., Nature 393, 185-187, 1998; Huang et al., submitted). In addition, incubating SR-VV or SR-Ad under conditions which restores the phospho-epitopes to the SR proteins regains their activity as splicing represser proteins. Here, we showed that that several genes were up-regulated in at least 50% chemoresistant AML patients, of which     

Assessment of circulating biochemical markers and antioxidative status in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients

Various circulating biochemical markers are indicators of pathological state in leukemia and its subtypes. Increased oxidative stress and decreased antioxidant factors portray clear image associated with malignancies during subtypes of leukemia. In this research work we investigated the inter-relationship among the subtypes of leukemia with circulating biochemical markers and oxidative stress in the Pakistani population. This research work was conducted on a total number of 70 subjects in which 20 were control participants and 50 were suffering from leukemia and divided into two subtypes (ALL and AML). Various circulating biomarkers were investigated including hematological, hepatic and renal profiles as well as oxidative stress markers, electrolytes and vitamins C and E. Results show that vitamin E was found to be decreased in diseased sub-types (P < 0.05). Malondialdehyde (MDA) levels were very high in disease sub-types (ALL-B = 8.69 ± 1.59; ALL-T = 8.78 ± 0.97; AML = 8.50 ± 1.29) compared to controls (1.22 ± 0.10; P < 0.05) while the levels of antioxidants [superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), catalase (CAT)], platelets, as well as electrolytes (Ca and Mg) were reduced in patients suffering from leukemia (sub-types). Enhanced levels of oxidative stress (MDA) and decreased levels of enzymatic and non-enzymatic antioxidants reflect the pathological state and impaired cell control in patients suffering from leukemia (subtypes) and show a strong correlation with oxidative stress, indicating that patients’ biological systems are under oxidative stress.     

Prognostic significance of chromosome analysis in de novo acute myeloid leukemia (AML)

Between 1981 and 1986 cytogenetic studies of bone marrow and/or blood cells in 139 patients with de novo acute myeloid leukemia (AML) were performed. The overall incidence of chromosomal aberrations was 53%, and this was not significantly influenced by sex, age nor the FAB classification. The aberrations most often found were: complex anomalies (n = 13), t(8; 21) (n = 10), trisomy 8 (n = 9), monosomy 7 (n = 6), monosomy 5, 5q-, trisomy 11, 12p- (n = 4) and trisomy 6, 11q-, inv (n = 3). The prognostic significance of chromosomal findings was evaluated in 112 patients treated by combination chemotherapy. The chromosomal status NN, AN, AA did neither significantly influence complete remission rate (NN: 68%, AN: 71%, AA: 60%) nor mean survival (NN: 24, AN: 26.6, AA: 35.6 months). On the other hand, certain types of chromosomal anomalies were of prognostic value. CR was obtained in all 10 patients with t(8; 21) but only in 2 out of 9 patients with complex aberrations. Median duration of CR in patients with t(8; 21) was significantly longer than in patients with a normal karyotype (30 vs 7 months).     

Mutation Patterns of 16 Genes in Primary and Secondary Acute Myeloid Leukemia (AML) with Normal Cytogenetics

Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML.