National Cancer Institute®
Last Modified: April 1, 2002
UI - 11565797
AU - Wan J; Wang J; Cheng H; Yu Y; Xing G; Oiu Z; Qian X; He F
TI - Proteomic analysis of apoptosis initiation induced by all-trans retinoic acid in human acute promyelocytic leukemia cells.
SO - Electrophoresis 2001 Aug;22(14):3026-37
AD - Department of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Chinese National Human Genome Center at Beijing, PR China.
The irreversible destiny of apoptosis in its early stage might play a critical role in the apoptosis of human acute promyelocytic leukemia (APL) cell line induced by all-trans retinoic acid (ATRA). To characterize protein alterations during the apoptosis-initiation phase and to understand the metabolic status at that time, we investigated the protein profiles in the apoptosis-initiation phase of APL cell line HL-60 by proteomic analysis. ATRA-withdrawal was conducted to demonstrate that there was committed initiation phase of apoptosis triggered by 10(-6) M ATRA at day 3. Only after that time point, ATRA-treated cells irreversibly went to apoptosis. Also at that time point, the positive regulators of apoptosis such as STAT3 increased at protein level, whereas negative regulators (Bcl-2 and p-STAT3) decreased. In addition, caspase-3 also increased after that time. Furthermore, comparative proteomic analysis was utilized to examine the protein expression profiles during the initiation stage of apoptosis. Our results showed 12 upregulated and 7 downregulated proteins experiencing twofold alteration, including key regulators of signal transduction such as G-proteins and nucleic receptors, proteins related with metabolism, oxidation and reduction, proteins associated with the nucleus and cytoskeleton-related proteins. Some of them could be positive modulators to trigger apoptosis, whereas others could contribute to intracellular defense against apoptosis induced by exogenous triggers. The results above suggest that there is a subtle balance between apoptosis and the intracellular defense against apoptosis. Once the balance is disturbed, cells would irreversibly initiate to undergo the execution of apoptosis.
UI - 11823047
AU - Re F; Arpinati M; Testoni N; Ricci P; Terragna C; Preda P; Ruggeri D;
TI - Senese B; Chirumbolo G; Martelli V; Urbini B; Baccarani M; Tura S; Rondelli D Expression of CD86 in acute myelogenous leukemia is a marker of dendritic/monocytic lineage.
SO - Exp Hematol 2002 Feb;30(2):126-34
AD - Institute of Hematology and Medical Oncology Seragnoli, University of Bologna, Bologna, Italy.
OBJECTIVE: The aim of this study was to determine whether expression of the CD86 costimulatory molecule in acute myeloid leukemia (AML) can identify blast cells committed to the monocytic/dendritic lineage. MATERIAL AND METHODS: One hundred ten consecutive AML patients observed at diagnosis were studied by flow cytometry. In selected experiments, in vitro cultures with CD34(+)CD86(+) or CD34(-)CD86(+) blasts were performed in the presence of granulocyte-macrophage colony-stimulating actor (GM-CSF) with or without tumor necrosis factor-alpha (TNF-alpha) or GM-CSF + interleukin-4 (IL-4), respectively, to induce a dendritic differentiation, documented by morphologic and immunophenotypic assays. T-cell alloreactivity to CD86(+) AML cells and leukemic dendritic cells (AML-DC) was tested in mixed leukocyte cultures and anti-leukemic cytotoxic assays. RESULTS: CD86 was expressed in 54% AML, whereas CD80 and CD1a were only occasionally positive. CD86(+) AML samples included M5 and M4, but also 47% M0-M1 FAB types, and were more frequently CD14(+) (p < 0.00001) and CD34(-) (p = 0.00005) than CD86(-)AML. Six different patterns of CD86(+) AML were identified, according to CD34 or CD14 total or partial coexpression. Four samples enriched in CD34(+)CD86(+) AML cells differentiated into AML-DC CD86(+), CD80(+), CD40(+), CD11c(+), HLA-DR(++), CD14(+/-) that also were CD1a(+) or CD83(+), after 6 days of in vitro culture with GM-CSF +/- TNF-alpha. CD34(-)CD86(+) AML cells differentiated into AML-DC after 3 to 5 days (n = 5 experiments), and trisomy 8 was found in two AML and AML-DC samples by fluorescence in situ hybridization analysis. Finally, AML-DC induced more potent allo-T-cell proliferation, cytokine release, and anti-leukemic cytotoxicity than CD86(+) blasts. CONCLUSIONS: In AML, CD86 is a marker of monocytic/dendritic lineage. Because CD86(+) blasts may differentiate into DC rapidly, CD86(+)AML patients could be optimal candidates for immunotherapy studies, both in autologous and allogeneic settings.
UI - 11823051
AU - Datta NS; Long MW
TI - Modulation of MDM2/p53 and cyclin-activating kinase during the megakaryocyte differentiation of human erythroleukemia cells.
SO - Exp Hematol 2002 Feb;30(2):158-65
AD - Department of Pediatrics and the Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
OBJECTIVE: This study was undertaken to address the involvement of CDK activating kinase (CAK), p53, and MDM2 proteins in the mitotic arrest associated with the acquisition of a polyploid DNA content during megakaryocyte differentiation of human erythroleukemia (HEL) cells. METHODS: To evaluate this mechanism we investigated HEL cells as a model system in which there is a marked increase in DNA content during megakaryocyte differentiation induced by phorbol-diesters. Specific cell-cycle phases were separated by centrifugal elutriation and SDS PAGE and Western analysis were performed to determine the relative abundance of these proteins. Kinase assays were carried out following immunoprecipitation of cellular lysates with the antibodies to the proteins. RESULTS: Polyploid HEL cells show an increase in the abundance of the CAK complex proteins, CDK7 and cyclin H, and a sixfold increase in CAK-specific activity. Increased CAK activity in polyploid HEL cells follows both the downregulation of p53 protein and its decreased association with CAK complex. Consistent with the reduction of p53, polyploid HEL cells undergo a dramatic increase in MDM2 protein abundance that in turn facilitates increased interaction of this protein with p53. CONCLUSION: These observations demonstrate that deregulated expression of MDM2 and p53 during megakaryocyte differentiation allow a relaxation of the control over genomic stability, allowing further replicative rounds of DNA synthesis.
UI - 11921270
AU - Karrison T; Archer KJ; Espinosa R 3rd; Wen M; Huo D
TI - Data management and statistical methods used in the analysis of balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and therapy-related acute leukemia: report from an international workshop.
SO - Genes Chromosomes Cancer 2002 Apr;33(4):346-61
AD - Department of Health Studies, University of Chicago, Chicago, Illinois 60637, USA. email@example.com
UI - 11921271
AU - Bloomfield CD; Archer KJ; Mrozek K; Lillington DM; Kaneko Y; Head DR;
TI - Dal Cin P; Raimondi SC 11q23 balanced chromosome aberrations in treatment-related myelodysplastic syndromes and acute leukemia: report from an international workshop.
SO - Genes Chromosomes Cancer 2002 Apr;33(4):362-78
AD - Division of Hematology and Oncology and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
Among 511 patients with therapy-related myelodysplastic syndrome or acute leukemia (t-MDS/t-AL) and balanced chromosome aberrations, 162 (32%) had translocations involving 11q23. The recurring translocation partners were 9p22 (48%), 19p13.3 (11%), 19p13.1 (10%), 4q21 (9%), 6q27 (6%), 1p32 (2%), 16p13.1 (2%), 10p13 (1%), and 17q25 (1%); in 9%, the translocations were seen only once. The remaining 349 patients were divided into five subgroups based on the balanced aberration: 21q22, inv(16), t(15;17), Rare, and Unique aberrations. Patients in the 11q23 subgroup had a sole cytogenetic abnormality more often than those in the 21q22, inv(16), Rare, and Unique subgroups, and a complex karyotype or -5/del(5q) and/or -7/del(7q) less often than patients in the 21q22, Rare, and Unique subgroups. Clinically, 11q23 patients had acute lymphoblastic leukemia (ALL) more often as their primary disease and a shorter latency from start of treatment for the primary disease to their t-MDS/t-AL diagnosis, except when compared with the inv(16) subgroup. The 11q23 subgroup demonstrated a younger age at t-MDS/t-AL diagnosis, but this finding was not significant when patients with AL as their primary diagnosis were excluded. Survival from the time of diagnosis of t-MDS/t-AL was significantly shorter for the 11q23 subgroup compared with that of the 21q22, inv(16), and t(15;17) subgroups (median 8 vs. 14, 28, and 29 months, respectively). Inferior survival occurred even though 11q23 patients were younger and more often received blood or marrow transplantation (BMT). Even among patients receiving BMT, 11q23 patients had a shorter median survival (9 vs. 12-31 months for the other subgroups). However, among 11q23 patients, those receiving BMT survived longer, with 1- and 5-year survivals of 43% and 18% compared with 23% and 7% for patients not transplanted. With regard to prior therapy, 11q23 patients, compared with other patients, received radiotherapy less often as their sole therapy and chemotherapy more often. They had received VP16, methotrexate, 6MP/6TG, L-asparaginase, daunorubicin, cytarabine, and VM26 more often, likely attributed to the high frequency of AL as their primary disease. More patients in the 11q23 subgroup had received doxorubicin, except in comparison with the 21q22 subgroup; more vincristine, except in comparison with the Rare and Unique subgroups; and more prednisone, except in comparison with the Unique subgroup. Patients in the 11q23 subgroup more often received alkylating agents (AAs) (86% vs. 59-82% for the other subgroups), and topoisomerase II inhibitors (TIs) (84% vs. 49-75%), and they more often reported exposure to AAs plus TIs without radiotherapy (33% vs. 12-21%), except in comparison with the 21q22 subgroup (36%). We performed a multivariate analysis to determine whether the adverse survival of 11q23 patients compared to other Workshop patients was explained by factors other than the presence of the 11q23 abnormality. Covariates in the final model were the five cytogenetic subgroup indicators, where the 11q23 subgroup was the referent (P < 0.0001); age at t-MDS/t-AL (P = 0.0036); previous exposure to lomustine (P < 0.0001) and mitoxantrone (P = 0.0225); BMT for t-MDS/t-AL (P = 0.0006); and karyotype complexity (P = 0.0114). The risk of death for 11q23 patients relative to patients in the 21q22, inv(16), t(15;17), and Unique subgroups was significant, even after adjustment for other risk factors (relative risks 2.3, 3.6, 3.1, and 1.5, respectively; P < 0.0001 for the first three comparisons and P = 0.0125 for the last). When a multivariable model was constructed, excluding patients with AL or MDS as their primary diagnosis, the relative risk of death for 11q23 patients was significantly higher than that of all five other cytogenetic subgroups. We conclude that among t-MDS/t-AL patients with balanced aberrations, 11q23 translocations are an independent adverse risk factor. Although BMT is the current therapy of choice, new treatment is required.
UI - 11921273
AU - Andersen MK; Larson RA; Mauritzson N; Schnittger S; Jhanwar SC;
TI - Pedersen-Bjergaard J Balanced chromosome abnormalities inv(16) and t(15;17) in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop.
SO - Genes Chromosomes Cancer 2002 Apr;33(4):395-400
AD - Cytogenetic Laboratory, Section of Hematology/Oncology, Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark. firstname.lastname@example.org
The Workshop identified 48 unselected patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML) and inv(16), and 41 patients with t(15;17) after chemotherapy (CT) and/or radiotherapy (RT) for a malignant or nonmalignant disease. The primary diseases were: breast cancer, 33 patients; lymphomas, 24 patients; various other solid tumors, 30 patients; and nonmalignant diseases, 2 patients. The general type of previous therapy was RT only in 10 patients with an inv(16) and in 12 patients with a t(15;17), alkylating agents plus topoisomerase II inhibitors in 24 patients with an inv(16) and in 18 patients with a t(15;17), topoisomerase II inhibitors only in 5 patients with an inv(16) and in 2 patients with a t(15;17), alkylating agents only in 6 patients in each subgroup, and other types of chemotherapy in 3 patients in each subgroup. Most CT-treated patients (69%) also received RT. The latency period to development of t-MDS/t-AML was short: a median of 22 months in patients with inv(16) and 29 months in patients with t(15;17). Twenty-six patients (54%) with an inv(16) and 17 patients (41%) with a t(15;17) had additional cytogenetic abnormalities, which were unrelated to age and survival in both subgroups. Trisomy of chromosomes 8, 21, and 22 and del(7q) were the most frequent additional abnormalities in the inv(16) subgroup, whereas +8, -5, and del(16q) were most frequent in the t(15;17) subgroup. The disease was overt t-AML in 38/48 patients (79%) with an inv(16) and in 38/41 patients (93%) with a t(15;17). Thirty-three of 39 intensively treated patients (85%) with an inv(16) obtained a complete remission, whereas 24 of 35 intensively treated patients (69%) with a t(15;17) obtained a complete remission. The median overall survival of intensively treated patients was 29 months in both cytogenetic subgroups. In the inv(16) subgroup, patients younger than 55 years of age had a longer survival when compared with older patients (P = 0.006). The study supports the observation that t-MDS/t-AML with inv(16) and t(15;17) is often associated with prior therapy with topoisomerase II inhibitors; however, a notable finding was the high frequency of treatment with only radiotherapy, 29% of t(15;17) and 21% of inv(16). Response rates to intensive chemotherapy in this study were comparable to those of de novo disease. Copyright 2002 Wiley-Liss, Inc.
UI - 11921274
AU - Block AW; Carroll AJ; Hagemeijer A; LM LM; van Lom K; Olney HJ; Baer MR
TI - Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an international workshop.
SO - Genes Chromosomes Cancer 2002 Apr;33(4):401-12
AD - Clinical Cytogenetics Laboratory, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. email@example.com
Seventy-seven patients were identified with Rare recurring (excluding 11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511 patients with treatment-related myelodysplastic syndromes and acute leukemia accepted from centers in the United States, Europe, and Japan. The abnormality subsets included 3q21q26 (17 patients), 11p15 (17 patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients), t(8;16)(p11;p13) (9 patients), and an "other" subset, which included t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3 patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients), t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with additional balanced and unbalanced rearrangements was observed in 70% of cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or 7 abnormalities were observed in 59%. The most frequent primary diseases were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients received alkylating agents plus topoisomerase II inhibitors with or without radiation therapy. The presenting diagnosis was t-AML in 47 cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven cases, five of whom had a t(9;22). The median latency time from initiation of original therapy to therapy-related disease diagnosis was quite long (69 months), and the overall median survival from the date of therapy-related disease diagnosis was very short (7 months). The 1-year survival rate was 34 +/- 7%, with no significant differences among subsets. Comparison with previously reported cases showed increased karyotypic complexity and adult presentation of pediatric-associated chromosome abnormalities. Copyright 2002 Wiley-Liss, Inc.
UI - 11921275
AU - Olney HJ; Mitelman F; Johansson B; Mrozek K; Berger R; Rowley JD
TI - Unique balanced chromosome abnormalities in treatment-related myelodysplastic syndromes and acute myeloid leukemia: report from an international workshop.
SO - Genes Chromosomes Cancer 2002 Apr;33(4):413-23
AD - Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA. firstname.lastname@example.org
A total of 123 balanced rearrangements, including 26 occurring as a sole anomaly, not known to be recurrent in myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) prior to the Workshop, were ascertained retrospectively from 104 patients with treatment-related MDS/AML (t-MDS/t-AML). Thirteen of the aberrations were reported previously in single cases and hence may be classified as recurrent as a result of the Workshop. Patients with Unique aberrations had complex karyotypes more often (P < 0.001 for all pairwise comparisons) than did other Workshop subgroups, with 72% having 3 or more aberrations. Among 85 cases with secondary chromosomal abnormalities, -5, -7, del(5q), and del(7q) were observed in 76%, which is significantly higher (P < or = 0.007 for all pairwise comparisons) than the frequencies found in the Workshop subgroups of patients with previously known recurring aberrations. The chromosome bands most often involved in balanced aberrations were 1p36 and 3q26-27. Treatment exposure was significantly different (less topoisomerase II inhibitor exposure, more radiotherapy-only exposure) than for patients with 11q23 (P < 0.001 and P = 0.002, respectively) and 21q22 (P = 0.007 and P = 0.002, respectively) abnormalities. The median time from the first toxic exposure to secondary disease, 59 months, was significantly longer (P < or = 0.016 for all significant pairwise comparisons) than the median latency of all other patients except those in the Rare subgroup, and the median survival time, 7 months, was significantly shorter than for patients in the 21q22, inv(16), and t(15;17) subgroups (P < or = 0.002 for all pairwise comparisons), but similar to patients in the 11q23 and Rare subgroups. In contrast to known recurring abnormalities, significantly more patients (61%, all P < 0.001) presented with t-MDS, with over one-third of these patients progressing to t-AML. Thus, this group of patients appears to be more similar to the typical t-MDS/t-AML patients, with complex karyotypes as well as chromosome 5 and 7 abnormalities, than to those with recurrent balanced rearrangements. Copyright 2002 Wiley-Liss, Inc.
UI - 8213633
AU - Kawano S; Tatsumi E; Yoneda N; Yamaguchi N
TI - Pattern of expression of CD45 RA/RO isoformic antigens in acute myeloblastic leukemia cells.
SO - Am J Clin Pathol 1993 Oct;100(4):386-93
AD - Department of Laboratory Medicine, Kobe University School of Medicine, Japan.
The authors used cell surface immunofluorescence to investigate the expression of CD45 RA (4KB5)/RO (UCHL1) antigen by acute myeloblastic leukemia (AML) cells from 78 patients. Four types--RA+/RO- (RO < 15%), RA-/RO+ (RA < 15%), mixed (20% RA and 20% RO), and RA-/RO- (RA < 10% and RO < 10%)--were observed. The number of cases with RA+/RO-, RA-/RO+, mixed, and RA-/RO- types in each French-American-British subclass of AML were as follows: M1 (n = 22): 18, 4, 0, 0; M2 (n = 21): 16, 0, 5, 0; M3 (n = 14): 11, 0, 0, 3; M4: 2, 2, 1, 0; and M5: 5, 5, 6, 0, respectively. The M1 RA-/RO+ type, which was always CD7- CD34- HLA-DR-, constituted a rare and distinct M1 subtype because there was no mixed type among the M1 cases. All CD7+ AML cells were the RA+/RO- type and HLA-DR+ except one. The expression of CD45 RO antigen, found in patients with M2, M4, and M5 subtypes of AML, was thought to be associated with the maturity of blasts as monocyte or granulocyte lineage cells. CD45 antigen has tyrosine phosphatase activity in association with nonreceptor-type tyrosine kinases. It was speculated that the functional status and stage of differentiation of the granulocyte/monocyte lineage determine which type of nonreceptor-type tyrosine kinases will operate, which then select the pattern of expression of the CD45 isoform. Thus, the determination of tyrosine kinases associated with CD45 isoforms seems to be important in understanding the AML subsets defined by the pattern of CD45 RA/RO expression.
UI - 8980370
AU - Arber DA; Glackin C; Lowe G; Medeiros LJ; Slovak ML
TI - Presence of t(8;21)(q22;q22) in myeloperoxidase-positive, myeloid surface antigen-negative acute myeloid leukemia.
SO - Am J Clin Pathol 1997 Jan;107(1):68-73
AD - Division of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA.
Although acute myeloid leukemias (AMLs) cytochemically negative for myeloperoxidase are now well recognized, myeloid surface antigen-negative AMLs are rare. The morphologic, cytochemical, immunologic, and cytogenetic or molecular features of such cases are described in four adults aged 19 to 60 years. All had AML with maturation (FAB M2) and were myeloperoxidase positive. Immunologic studies showed all to be HLA-DR positive but negative for the CD13, CD14, and CD33 antigens. Two of four were CD34 antigen positive. Cytogenetic studies were performed in three patients, and all demonstrated t(8;21)(q22;q22). In studies using the reverse transcriptase polymerase chain reaction in two patients, including the patient in whom karytypic analysis was not performed, the AML1-ETO fusion product of t(8;21) was identified. These findings suggest an association between the lack of myeloid antigen expression in myeloperoxidase-positive AML and the presence of t(8;21). In addition, the results demonstrate the continued need for cytochemical studies in the evaluation of acute leukemias.
UI - 11836165
AU - Domingo-Claros A; Larriba I; Rozman M; Irriguible D; Vallespi T; Aventin
TI - A; Ayats R; Milla F; Sole F; Florensa L; Gallart M; Tuset E; Lopez C; Woessner S Acute erythroid neoplastic proliferations. A biological study based on 62 patients.
SO - Haematologica 2002 Feb;87(2):148-53
AD - Ciudad Sanitaria y Universitaria de Bellvitge, L'Hospitalet del Llobregat 08907, Barcelona, Spain. email@example.com
BACKGROUND AND OBJECTIVES: The terms acute erythroleukemia and AML-M6 are defined in the FAB classification as proliferations of dysplastic erythroid elements mixed with blasts of myeloid origin, but pure erythroid leukemias are not included. The recent WHO classification has a category of acute myeloid leukemia not otherwise categorized, which includes acute erythroid leukemia (M6) of two subtypes: M6a-erythroleukemia (erythroid/myeloid) and M6b-pure erythroid leukemia. The aims of this co-operative study were to discover the incidences of these different subtypes, and pay special attention to the morphology of these entities. DESIGN AND METHODS: We reviewed a series of 62 patients with erythroid neoplastic proliferations. Previous medical history, age, sex, peripheral blood and bone marrow cell counts, cytochemical stains, immunophenotype, and cytogenetics were evaluated at presentation. We analyzed the incidence of erythrocyte, leukocyte and platelet abnormalities in the peripheral blood. In bone marrow we analyzed dysplastic features of erythroblasts, granulocytic elements and the megakaryocytic lineage. RESULTS: Fifty-three patients met the criteria of M6a subtype of the WHO classification, and 2 were classified as having pure erythremia (M6b); 7 cases could not be classified according to the WHO criteria. Fifty-five patients presented with de novo acute leukemia, and seven patients had secondary acute leukemia. The most frequent dysplastic features in blood smears were: schistocytes, tear-drop and pincered cells in erythrocytes; hypogranulation and hyposegmentation in leukocytes; gigantism and hypogranulation in platelets. In bone marrow, megaloblastic changes, multinuclearity, karyorrhexis and basophilic stippling in erythroblasts; hypogranulation and gigantism in granulocytic series, and micromegakaryocytes and unconnected nuclei in megakarocytes were the most dysplastic features. A positive PAS reaction and increase of bone marrow iron with ring sideroblasts were common features. Trilineage dysplasia was present in 54% of cases. Dysplastic features in granulocytic elements were absent in 26% of patients and minimal erythroblastic dysplasia was observed in seven patients. A complex karyotype was seen in 27% of patients; chromosomes 5 and 7 were the most frequently involved. INTERPRETATION AND CONCLUSIONS: De novo acute erythroid leukemia was more frequent than secondary cases in our series. The most frequent type of acute erythroid proliferation was the WHO M6a subtype and the least the pure erythroid leukemia. We found a group of seven patients (11%) who could not be classified according to the WHO criteria. Morphologic findings of erythrocytes in peripheral blood, such as schistocytes, tear-drop and pincered cells, were outstanding features. Morphologic aspects remain one of the most important tools for diagnosing these entities.
UI - 11914187
AU - Reynolds P; Von Behren J; Elkin EP
TI - Birth characteristics and leukemia in young children.
SO - Am J Epidemiol 2002 Apr 1;155(7):603-13
AD - California Department of Health Services, Environmental Health Investigations Branch, Oakland, CA 94612, USA. firstname.lastname@example.org
The relation between birth characteristics and leukemia in young children was investigated in a large population-based study in California. Cases were obtained from the statewide cancer registry for 1988-1997. During this time, 1,957 leukemia cases were diagnosed among children under age 5 years. Of these, 1,728 (88%) were matched to a California birth certificate. Two control birth certificates, matched on date of birth and sex, were randomly selected from the statewide birth registry for each case. Analyses were performed separately for acute lymphoid leukemia (ALL) and acute nonlymphoid leukemia (ANLL). Odds ratios and 95% confidence intervals were estimated from conditional logistic regression. The strongest finding was for greatly increased risk of both types of leukemia in children with Down's syndrome (22 cases and no controls). African-American children had strikingly decreased risk for ALL (odds ratio (OR) = 0.29, 95% confidence interval (CI): 0.20, 0.42), and Asian/Pacific Islanders had increased risk for ANLL (OR = 2.00, 95% CI: 1.19, 3.36). Older maternal age was associated with slightly increased risk for ALL (maternal age > or =35 years, OR = 1.25, 95% CI: 1.04, 1.52), although this odds ratio was somewhat reduced when adjusted for other factors. No strong relations were observed for birth weight and ALL or ANLL.
UI - 11789265
AU - Tan H; Hao Y; Ying H
TI - [Study on human leukemia cell apoptosis inducing effect of fraction C of Naja naja Actra Venom]
SO - Zhongguo Zhong Xi Yi Jie He Za Zhi 2000 Apr;20(4):272-5
AD - Second Affiliated Hospital of Guangzhou Medical College, Guangzhou (510260).
OBJECTIVE: To study the effect and mechanism of fraction C isolated from Naja naja Actra Venom (FCNNAV) in inducing apoptosis of human leukemia cells. METHODS: Light microscope, transmission electron microscope, DNA electrophoresis, flow cytometry and RT-PCR assay were used to observe the changes of human leukemia cells in morphology and biochemistry, and Bcl-2/Bax expression after exposing to FCNNAV. RESULTS: FCNNAV could induce HL60 cells apoptosis demonstrated by the typical morphological and biochemical changes. Flow cytometry showed that J6-1, K562, HL60 and fresh leukemia cells apoptosis could be induced by FCNNAV, and the apoptosis rate was dose-dependent. RT-PCR detection showed the Bcl-2 gene expression of HL60 cells was down-regulated by FCNNAV, whereas the Bax expression was unaffected. CONCLUSION: FCNNAV could induce apoptosis of human leukemia cells and this effect is related to down-regulation of Bcl-2 gene expression level.
UI - 11930663
AU - Li Y; Yang L; Chen S; Li R; Zhang Y; Lu Y; Luo G
TI - Clonal expansion T cells identified in acute monoblastic leukemia by CDR3 size analysis of TCR V beta repertoire using RT-PCR and genescan.
SO - Chin Med J (Engl) 2002 Jan;115(1):69-71
AD - Institute of Hematology, Medical College, Jinan University, Guangzhou 510632, China.
OBJECTIVE: To investigate the distribution and clonality of T cell receptor (TCR) V beta repertoire in patients with acute monoblastic leukemia (AML-M5). METHODS: Expression of the TCR V beta repertoire was analyzed using reverse transcription-polymerase chain reaction (RT-PCR), which amplified the complementarity determining region 3 of 24 TCR V beta genes in peripheral blood from 9 cases with acute myclogenous leukemia subtype 5 or acute monoblastic leukemia (AML-M5). PCR products were further studied by genescan analysis to identify T cell clonality. RESULTS: Expression of 1-10 V beta subfamilies was found in samples from 9 patients. Genescan analysis showed that some V beta subfamily products from 8 of 9 cases contained an oligoclonal peak. Oligoclonal T cells of the V beta 2 subfamily could be found in 6 patients with AML-M5. CONCLUSIONS: T cell clonality expansion was found in AML-M5 cases and were tendentious in the V beta 2 subfamily, suggesting a the specific immune response for leukemia cell (M5) associated antigen and may display antileukemia activity.
UI - 11925725
AU - Pigneux A; Marit G
TI - [Acute myeloblastic leukemia]
SO - Rev Prat 2002 Feb 1;52(3):327-31
AD - Service des maladies du sang, centre hospitalier universitaire de Bordeaux, hopital du Haut-Leveque, 33604 Pessac.
UI - 11939742
AU - Nagendra S; Meyerson H; Skallerud G; Rosenthal N
TI - Leukemias resembling acute promyelocytic leukemia, microgranular variant.
SO - Am J Clin Pathol 2002 Apr;117(4):651-7
AD - Department of Pathology, University of Iowa College of Medicine, Iowa City, USA.
Acute promyelocytic leukemia (APL) should be distinguished from other subtypes of acute myeloid leukemia (AML) because of the increased risk of disseminated intravascular coagulation (DIC) and its response to arsenic compounds and retinoids. Some cases of AML seem morphologically similar to the microgranular variant of APL (French-American-British [FAB] AML-M3v) but lack the t(15;17). We evaluated 8 cases of APL-like leukemias for subtle morphologic, cytochemical, immunophenotypic, and cytogenetic differences compared with 5 cases of promyelocytic leukemia/retinoic receptor alpha (PML/RARalpha)-positive APL (FAB AML-M3v). We also evaluated both groups for the presence of DIC. No differences among the groups were noted in blast size, chromatin pattern, nuclear morphologic features, intensity of myeloperoxidase staining, or presence of Auer rods. Immunophenotypes were similar; both types of cases lacked CD34 and HLA-DR and were CD13+ and CD33+. Two cases of APL-like leukemias also were CD56+. DIC was present in 2 patients with M3v. Our study shows that there are no definitive morphologic, cytochemical, or immunophenotypic findings that can distinguish these cases from PML/RARalpha-positive APL.
UI - 7869766
AU - Belka C; Ahlers A; Sott C; Gaestel M; Herrmann F; Brach MA
TI - Interleukin (IL)-6 signaling leads to phosphorylation of the small heat shock protein (Hsp)27 through activation of the MAP kinase and MAPKAP kinase 2 pathway in monocytes and monocytic leukemia cells.
SO - Leukemia 1995 Feb;9(2):288-94
AD - Max-Delbruck-Center for Molecular Medicine, Free University of Berlin, Universitatsklinikum Rudolf Virchow, Germany.
Interleukin-6 is a multifunctional cytokine which regulates various aspects of the host immune response. Here we show that signaling events transferred by IL-6 in monocytes and the U937 human monocytic leukemia cell line lead to the phosphorylation of the small heat shock protein (Hsp)27. Phosphorylation of Hsp27 is both dose- and time-dependent. In the absence of NaF, a serine/threonine phosphatase inhibitor, IL-6 failed to initiate Hsp27 phosphorylation in vitro. IL-6 also failed to phosphorylate Hsp27 when cells had been deactivated with tyrosine kinase inhibitors such as genistein. The capacity of cellular extracts to phosphorylate Hsp27 could be, however, restored when either immunoprecipitated activated MAP kinase or purified MAPKAP kinase 2 was added to cell lysates. These findings suggest that IL-6-mediated phosphorylation of Hsp27 results from activation of MAPKAP kinase 2, a serine/threonine kinase which is activated by MAP kinase. Taking together, our findings indicate that IL-6-induced activation of MAP kinase by IL-6 entails the activation of MAPKAP kinase 2 and subsequent phosphorylation of the Hsp27.
UI - 7780153
AU - Shurtleff SA; Meyers S; Hiebert SW; Raimondi SC; Head DR; Willman CL;
TI - Wolman S; Slovak ML; Carroll AJ; Behm F; et al Heterogeneity in CBF beta/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia.
SO - Blood 1995 Jun 15;85(12):3695-703
AD - Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Inv(16)(p13q22) is one of the most frequent chromosomal rearrangements found in acute myelogenous leukemia (AML), representing approximately 16% of documented karyotypic abnormalities. The inv(16) breakpoints have been cloned and shown to involve the non-DNA binding component of the AML-1 transcription factor complex termed core binding factor beta gene (CBF beta) on 16q and the smooth muscle myosin heavy chain gene (MYH11) on 16p. In this study, we analyzed 37 cases of inv(16)-containing AML and 4 cases with t(16;16)(p13;q22) for expression of the CBF beta/MYH11 chimeric message by reverse transcription-polymerase chain reaction (PCR) analysis. CBF beta/MYH11 chimeric messages were detected in 33 of 37 cases with the inv(16) and in the 4 t(16;16)-containing cases. Sequence analysis of PCR products showed extensive breakpoint heterogeneity in both CBF beta and MYH11. In addition to the previously described breakpoint in CBF beta at nucleotide (nt) 495 (amino acid 165), we have identified a second novel fusion point at nt 399 (amino acid 133) in 7% of the cases. Similarly, a unique breakpoint site was identified in MYH11 at nt 1098, as well as at three previously characterized sites at nts 994, 1201, and 1921. Of the 4 PCR-negative cases, 2 of 3 tested lacked CBF beta rearrangements by Southern blot analysis, suggesting the possible involvement of a different genomic locus in some cases with cytogenetic evidence of inv(16). To assess whether the portions of CBF-beta contained within the CBF beta/MYH11 chimeric products retain the ability to interact with their heterodimeric DNA-binding partner AML-1, we performed in vitro DNA-binding analysis. Recombinant CBF-beta polypeptides consisting of the N-terminal 165 amino acids retained their ability to interact with AML-1, whereas mutants containing only the N-terminal 133 amino acids interacted with AML-1 less efficiently. These data suggest that different CBF beta/MYH11 products may vary subtly in their biologic activities.
UI - 7795233
AU - van der Reijden BA; Lombardo M; Dauwerse HG; Giles RH; Muhlematter D;
TI - Bellomo MJ; Wessels HW; Beverstock GC; van Ommen GJ; Hagemeijer A; et al RT-PCR diagnosis of patients with acute nonlymphocytic leukemia and inv(16)(p13q22) and identification of new alternative splicing in CBFB-MYH11 transcripts.
SO - Blood 1995 Jul 1;86(1):277-82
AD - Department of Human Genetics, Leiden University, Sylvius Laboratories, The Netherlands.
As acute nonlymphocytic leukemia (ANLL) with inv(16) (p13q22) or t(16;16)(p13;q22) has been shown to result from the fusion of transcription factor subunit core binding factor (CBFB) to a myosin heavy chain (MYH11), we sought to design methods to detect this rearrangement using reverse transcriptase-polymerase chain reaction (RT-PCR). In all of 27 inv(16)(p13q22) and four t(16;16)(p13;q22) cases tested, a chimeric CBFB-MYH11 transcript coding for an in-frame fusion protein was detected. In a more extensive RT-PCR analysis with different primer pairs, we detected a second new chimeric CBFB-MYH11 transcript in 10 of 11 patients tested. The CBFB-MYH11 reading frame of the second transcript was maintained in one patient but not in the others. We show that the different CBFB-MYH11 transcripts in one patient arise from alternative splicing. Translation of the transcript in which the CBFB-MYH11 reading frame is not maintained leads to a slightly truncated CBFB protein.
UI - 7670094
AU - Atkins KB; Troen BR
TI - Comparative responsiveness of HL-60, HL-60R, and HL-60R+ (LRARSN) cells to retinoic acid, calcitriol, 9 cis-retinoic acid, and sodium butyrate.
SO - Blood 1995 Oct 1;86(7):2475-80
AD - Department of Internal Medicine, Veterans Administration Medical Center, Ann Arbor, MI, USA.
In HL-60 cells, retinoic acid (RA) and 9 cis-RA induce granulocytic differentiation, and calcitriol and sodium butyrate induce monocytic differentiation. To study the role of retinoid resistance on the response to these agents, we investigated their effects in HL-60 cells, retinoid-resistant HL-60R cells, and HL-60R+ cells in which retinoid sensitivity has been restored. In HL-60 cells, cathepsin D (ctsd) mRNA levels are increased by these agents and by cholera toxin after pretreatment with each agent. Calcitriol, 9 cis-RA, and sodium butyrate increase interleukin-8 (IL-8) mRNA expression, and pretreatment with these agents or RA potentiates the stimulation of IL-8 by phorbol ester (TPA). Pretreatment of HL-60 cells with all of the agents confers inducibility of cathepsin L (ctsl) mRNA by TPA in previously unresponsive cells. In HL-60R cells, none of the agents alone or in combination significantly enhances the expression of the ctsd, IL-8, or ctsl mRNAs. Retinoid stimulation (either alone or in combination with the other agents) of the three mRNAs is partially restored in the HL-60R+ cells. Calcitriol does not alter the expression of any of these mRNAs, and only the stimulation of IL-8 mRNA by sodium butyrate is recovered. Treatment with all of the agents inhibits proliferation and stimulates differentiation of the HL-60 cells. RA and calcitriol are unable to inhibit proliferation of the HL-60R cells, whereas only calcitriol fails to inhibit proliferation of the HL-60R+ cells. None of the agents induces differentiation in either the HL-60R or HL-60R+ cells. Therefore, the mutation of the RA receptor alpha is insufficient to account for the altered responses of the HL-60R cells, and there are likely defects in other signaling pathways in these cells. These cells may prove useful in examining the mechanism of cross-resistance between various differentiating agents.
UI - 9447846
AU - van der Reijden BA; Bloomfield CD; Touw IP; Jansen JH
TI - Acute leukemias with structurally altered core binding factor subunits Netherlands.
SO - Leukemia 1997 Dec;11(12):2217-9
AD - Institute of Hematology, Erasmus University Rotterdam, The Netherlands.
In the summer of 1997, the first meeting on 'Acute Leukemias with Structurally Altered Core Binding Factor Subunits' was held. During the meeting, which attracted more than 140 participants, many recognized experts in the field of CBF and leukemia were present. In this short report we summarize new data on CBF involvement in leukemia and other diseases that were presented during the meeting.
UI - 11179492
AU - Ohyashiki JH; Hayashi S; Yahata N; Iwama H; Ando K; Tauchi T; Ohyashiki
TI - K Impaired telomere regulation mechanism by TRF1 (telomere-binding protein), but not TRF2 expression, in acute leukemia cells.
SO - Int J Oncol 2001 Mar;18(3):593-8
AD - First Department of Internal Medicine, Tokyo Medical University, Shinjuku-ku, Tokyo 160-0023, Japan.
Telomere regulation is suggested to be an important mechanism in cellular proliferation and cellular senescence not only in normal diploid cells but also in neoplastic cells, including human leukemia cells. We studied the possible correlation among telomere length, telomerase (a ribonuclear protein that synthesizes the telemeres de novo) activity, hTERT (a catalytic subunit of telomerase) expression, and TRF1 and TRF2 (telomere DNA binding proteins) expression in human acute leukemia cells. The hTERT expression level was strongly associated with telomerase activity (P=0.0001), indicating that the expression level of the catalytic subunit (hTERT) regulates telomerase activity in human acute leukemia cells. TRF1 expression, which is believed to control telomere length, was significantly elevated in patients with acute lymphoblastic leukemia (ALL) (P=0.0232) compared to those in acute myeloid leukemia (AML); TRF1 expression tended to be higher in patients without telomere shortening (P=0.077) and in those with hTERT expression (P=0.055). This indicates that TRF1 may act to monitor telomere length under the condition of up-regulated telomerase activity in some neoplastic cells. In contrast, TRF2 expression in acute leukemia did not show any correlation with telomere parameters in this study. Although the precise regulation mechanism of telomere length is still uncertain, these results may suggest that regulation of telomere length is partially associated with TRF1 expression, whereas dysfunction of TRF1 expression may be speculated in a subset of acute leukemia.
UI - 11745387
AU - Zocchi MR; Pellegatta F; Pierri I; Gobbi M; Poggi A
TI - Leukocyte-associated Ig-like receptor-1 prevents granulocyte-monocyte colony stimulating factor-dependent proliferation and Akt1/PKB alpha activation in primary acute myeloid leukemia cells.
SO - Eur J Immunol 2001 Dec;31(12):3667-75
AD - Laboratory of Tumor Immunology, Department of Internal Medicine, Scientific Institute San Raffaele, Milan, Italy.
The leukocyte-associated Ig-like receptor-1 (LAIR-1), a surface leukocyte receptor containing two immune receptor tyrosine-based inhibitory motif (ITIM) is expressed on acute myeloid leukemia (AML) blasts isolated from peripheral blood or bone marrow of 17 patients (2 M0, 3 M1, 5 M2, 2 M4 and 5 M5 according to French, American and British classification). Further, we provide evidence thatLAIR-1 engagement inhibits granulocyte-monocyte colony-stimulating factor (GM-CSF)-induced proliferation of AML blasts. Indeed, leukemia cells stimulated with GM-CSF were blocked in the G0/G1 phase of the cell cycle and underwent apoptosis within 4 days after the engagement of LAIR-1. Remarkably, LAIR-1 was functional also in AML blasts which do not express CD33, mainly M4 and M5. Importantly, the LAIR-1 ligation led to a strong inhibition of both GM-CSF receptor-mediated intracellular calcium increases, phosphorylation and activation of Akt1/protein kinase B alpha, a substrate of the phosphatidylinositol-3 kinase. This last inhibitory effect was prevented by a synthetic peptide spanning the ITIM portion of LAIR-1, suggesting the involvement of SHP-1 phosphatase in LAIR-1-mediated inhibitory signal. Altogether, these findings indicate that the engagement of LAIR-1 can down-regulate GM-CSF-mediated survival and proliferation of AML blasts, suggesting an additional therapeutic approach to the treatment of AML patients.
UI - 11911279
AU - Bruel A; Paschke S; Jainta S; Zhang Y; Vassy J; Rigaut J P; Beil M
TI - Remodeling of vimentin cytoskeleton correlates with enhanced motility of promyelocytic leukemia cells during differentiation induced by retinoic acid.
SO - Anticancer Res 2001 Nov-Dec;21(6A):3973-80
AD - Institute of Hematology, Hospital St. Louis, Paris, France. email@example.com
The intermediate filament (IFs) cytoskeleton is one of the major determinants for the mechanical properties of cytoplasm. Vimentin is the major IFs protein in peripheral blood neutrophils. We investigated its expression and function during neutrophil differentiation using the promyelocytic leukemia cell line NB4. The differentiation of NB4 cells along the neutrophil lineage and the monocytic pathway was induced by all-trans retinoic acid (ATRA) and phorbol esters (PMA), respectively. We demonstrated a down-regulation of vimentin after ATRA treatment of NB4 cells by immunoblotting and immunofluorescence. The architecture of the vimentin cytoskeleton in differentiated NB4 cells resembled that observed in mature neutrophils. In contrast, we showed a slight increase of vimentin content in phorbol ester (PMA)-treated NB4 cells. The structural features of the vimentin cytoskeleton obtained by image analysis showed significant differences in network density and directionality between ATRA-treated NB4 cells and controls. The functional consequence of the cytoskeletal remodeling for the mechanical properties of NB4 cells was assessed in migration assays. After ATRA treatment, we found a 4-fold increased migration of NB4 cells across transwell membranes with a 8 microm pore size without any cell size modification. No significant differences between PMA-treated NB4 cells and control cells could be observed using similar tests. These results indicate that both vimentin expression and network architecture are tightly controlled during neutrophil differentiation to regulate the mechanical properties of these cells.
UI - 11921279
AU - Langabeer SE; Gale RE; Rollinson SJ; Morgan GJ; Linch DC
TI - Mutations of the AML1 gene in acute myeloid leukemia of FAB types M0 and M7.
SO - Genes Chromosomes Cancer 2002 May;34(1):24-32
AD - Department of Haematology, University College London, London, United Kingdom. firstname.lastname@example.org
The AML1 gene encodes a transcription factor that, together with its heterodimeric partner CBFB, regulates a number of target genes that are essential for normal hemopoiesis. In acute myeloid leukemia (AML), AML1 is disrupted not only by chromosomal translocations but also by mutations in the runt domain, which binds both DNA and CBFB. Acquired mutations have been described predominantly in the AML FAB type M0. To date, most patients appear to have biallelic disease, suggesting a complete lack of normal AML1 function. Inherited loss of function mutations thought to lead to haploinsufficiency also have been described in patients who have a familial disorder with predisposition to AML (FPD/AML), indicating the role of AML1 in megakaryopoiesis. Using single-strand conformation polymorphism analysis, we studied the AML1 runt domain in 41 patients with M0 AML and identified potentially pathologic mutations in five (12%). Biallelic disease could be confirmed in only one patient, using loss of heterozygosity studies. At least three of the