National Cancer Institute®
Last Modified: April 1, 2002
UI - 11875699
AU - Murray L; McCarron P; Bailie K; Middleton R; Davey Smith G; Dempsey S;
TI - McCarthy A; Gavin A Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study.
SO - Br J Cancer 2002 Feb 1;86(3):356-61
AD - Northern Ireland Cancer Registry, Department of Epidemiology and Public Health, The Queens University, Belfast, Riddel Hall, Stranmillis Road, Belfast BT9 5EE, UK. email@example.com
In a historical cohort study of all singleton live births in Northern Ireland from 1971-86 (n=434,933) associations between early life factors and childhood acute lymphoblastic leukaemia were investigated. Multivariable analyses showed a positive association between high paternal age (> or =35 years) and acute lymphoblastic leukaemia (relative risk=1.49; 95% confidence interval (CI)=0.96--2.31) but no association with maternal age. High birth weight (> or =3500 g) was positively associated with acute lymphoblastic leukaemia (relative risk=1.66; 95% CI=1.18--2.33). Children of mothers with a previous miscarriage or increased gestation (> or =40 weeks) had reduced risks of ALL (respective relative risks=0.49; 95% CI=0.29--0.80, and 0.67; 95% CI=0.48--0.94). Children born into more crowded households (> or =1 person per room) had substantially lower risks than children born into less crowded homes with also some evidence of a lower risk for children born into homes with three adults (relative risks=0.56; 95% CI=0.35-0.91 and 0.58; 95% CI=0.21-1.61 respectively). These findings indicate that several early life factors, including living conditions in childhood and maternal miscarriage history, influence risk of acute lymphoblastic leukaemia in childhood. Copyright 2002 The Cancer Research Campaign
UI - 11748675
AU - Foliart DE; Iriye RN; Tarr KJ; Silva JM; Kavet R; Ebi KL
TI - Alternative magnetic field exposure metrics: relationship to TWA, appliance use, and demographic characteristics of children in a leukemia survival study.
SO - Bioelectromagnetics 2001 Dec;22(8):574-80
AD - Public Health Institute, Berkeley, California, USA. firstname.lastname@example.org
The ongoing Childhood Leukemia Survival Study is examining the possible association between magnetic field exposure and survival of children with newly diagnosed acute lymphocytic leukemia (ALL). We report the results of the first year 24 h personal magnetic field monitoring for 356 US and Canadian children by time weighted average TWA and alternative exposure metrics. The mean TWA of 0.12 microT was similar to earlier personal exposure studies involving children. A high correlation was found between 24 h TWA and alternative metrics: 12 h day TWA, 12 night TWA, geometric mean, 95th percentile value, percentage time over 0.2 and 0.3 microT, and an estimate of field stability (Constant Field Metric). Two measures of field intermittency, rate of change metric (RCM) and standardized rate of change metric (RCMS), were not highly correlated with TWA. The strongest predictor of TWA was location of residence, with highest TWAs associated with urban areas. Residence in an apartment, lower paternal educational level, and residential mobility were also associated with higher TWAs. There were no significant differences in the appliance use patterns of children with higher TWA values. Children with the highest field intermittency (high RCM) were more likely to sit within 3 feet of a video game attached to the TV. Our results suggest that 24 h TWA is a representative metric for certain patterns of exposure, but is not highly correlated with two metrics that estimate field intermittency. Copyright 2001 Wiley-Liss, Inc.
UI - 11801462
AU - Bolufer P; Barragan E; Verdeguer A; Cervera J; Fernandez JM; Moreno I;
TI - Lerma E; Esquembre C; Tasso M; Fuster V; Bermudez M; Sanz MA Rapid quantitative detection of TEL-AML1 fusion transcripts in pediatric acute lymphoblastic leukemia by real-time reverse transcription polymerase chain reaction using fluorescently labeled probes.
SO - Haematologica 2002 Jan;87(1):23-32
AD - Laboratorio de Biologia Molecular, (Lab Hormonas), C Maternal Hospital Universitario La Fe, Avda Campanar 21, 46009 Valencia, Spain. email@example.com
BACKGROUND AND OBJECTIVES: We report a new real-time reverse transcription polymerase chain reaction (RT-PCR) method for quantification of TEL-AML1 transcripts. The method is based on hybridization probe (HybProbe) chemistry applied in LightCycler equipment. The study group comprised 44 successive cases of pediatric acute lymphoblastic leukemia (P-ALL). DESIGN AND METHODS: The quantitative estimation of TEL-AML1 transcripts was performed in 10 P-ALL TEL-AML1-positive patients. The PCR was performed in capillary tubes in 10 microL final volumes using two sets of primers: M1, which detects the long (L-form) and short (S-form) transcripts, and M2, specific for the L-form. The fluorescently labeled HybProbes (TEL 3FL and TEL 5LC) hybridize to the TEL region. TEL-AML1 expression was normalized relative to the levels of AML1 transcripts. Standard curves were prepared using serial dilutions of plasmids with TEL-AML1 or AML1 inserts. RESULTS: The sensitivity attained allowed the detection of TEL-AML1 transcripts at a 10-4 dilution of a cDNA sample from a patient at diagnosis. The within-assay coefficient of variation (CV) for TEL-AML1 was 7.0% and the between-assay CV was 13%. Levels of TEL-AML1 transcript and the TEL-AML1/AML1 ratio decreased by more than four log units (p <0.001) during or after the course of initial treatment. Most of the patients who achieved complete remission after 5-6 months of initial treatment were TEL-AML1 negative, although some positive samples with negligible amounts of TEL-AML1 transcripts were still detected. INTERPRETATION AND CONCLUSIONS: This method has the sensitivity and reliability required to monitor the presence of minimal residual disease, and could be a powerful tool in monitoring the efficacy of the response to chemotherapy.
UI - 11849208
AU - Wright AM; Paterson AR; Sowa B; Akabutu JJ; Grundy PE; Gati WP
TI - Cytotoxicity of 2-chlorodeoxyadenosine and arabinosylcytosine in leukaemic lymphoblasts from paediatric patients: significance of cellular nucleoside transporter content.
SO - Br J Haematol 2002 Mar;116(3):528-37
AD - Department of Pharmacology, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada.
2-chlorodeoxyadenosine (2-CdA) and arabinosylcytosine (araC) are nucleoside drugs that are used to treat various leukaemias, although 2-CdA has not been tested extensively in children with acute lymphoblastic leukaemia (ALL). Nucleoside cytotoxicity depends on the conversion of these agents to 5'-phosphate derivatives, following drug entry into cells via nucleoside transport (NT) processes. This study compared es nucleoside transporter content, determined using a flow cytometric assay with SAENTA [5'-S-(2-aminoethyl)-N6-(4-nitrobenzyl)-5'-thioadenosine] fluorescein, and cytotoxicities of 2-CdA and araC in fresh lymphoblasts from previously untreated paediatric ALL patients and the human T-lymphoblast cell line, CCRF-CEM. Lymphoblast samples from individual patients ranged widely in sensitivity to both 2-CdA (IC50, 6 nmol/l to > 5 micromol/l; mean = 418 nmol/l; n = 8) and araC (IC50, 59 nmol/l to > 5 micromol/l; mean = 1050 nmol/l; n = 7), although IC50 values for the two drugs were correlated (r = 0.78, P = 0.032, n = 7). Cellular es nucleoside transporter content varied more than 35-fold among samples from 10 patients. The correlation between es nucleoside transporter content and drug sensitivity was statistically significant for araC (r = -0.93, P = 0.023, n = 5), but not for 2-CdA (r = -0.57, P = 0.23, n = 6). Exposure of CCRF-CEM cells to araC resulted in a substantial araC concentration-dependent increase in the relative survival of es transporter-deficient cells, whereas the increase was slight following exposure to 2-CdA. We conclude that, in ALL lymphoblasts, es nucleoside transporter content is a determinant of araC sensitivity and that a deficiency in NT may impart resistance to araC.
UI - 11880754
AU - Axelson O; Fredrikson M; Akerblom G; Hardell L
TI - Leukemia in childhood and adolescence and exposure to ionizing radiation in homes built from uranium-containing alum shale concrete.
SO - Epidemiology 2002 Mar;13(2):146-50
AD - Division of Occupational and Environmental Medicine, Department of Health and Environment, Linkoping University, Linkoping, Sweden. firstname.lastname@example.org
Concerns in Sweden about indoor radon around 1980 prompted measurements of gamma-radiation from the facades of houses to identify those constructed of uranium-containing alum shale concrete, with potentially high radon concentrations. To evaluate any possible risk of acute lymphocytic leukemia from exposure to elevated gamma-radiation in these homes, we identified the acute lymphocytic leukemia cases less than 20 years of age in Sweden during 1980-1989 as well as eight controls per case from the population registry, matching on age, gender, and county. Using the existing measurements, exposure was assessable for 312 cases and 1,418 controls from 151 properly measured municipalities. A conditional logistic odds ratio of 1.4 (95% confidence interval = 1.0-1.9) was obtained for those ever having lived in alum shale concrete houses, with the average exposure exceeding 0.10 microsieverts per hour. Comparing those who ever lived in alum shale concrete houses (divided by higher and lower annual average exposure) with those who never lived in such houses, we found a weak dose-response relation. The results suggest some risk of acute lymphocytic leukemia from indoor ionizing radiation among children and young adults.
UI - 11920508
AU - Ohnita K; Isomoto H; Mizuta Y; Maeda T; Haraguchi M; Miyazaki M; Murase
TI - K; Murata I; Tomonaga M; Kohno S Helicobacter pylori infection in patients with gastric involvement by adult T-cell leukemia/lymphoma.
SO - Cancer 2002 Mar 1;94(5):1507-16
AD - Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
BACKGROUND: Gastrointestinal involvement is seen frequently in patients with adult T-cell leukemia/lymphoma (ATLL). The authors previously showed a relatively low prevalence of Helicobacter pylori infection in individuals with human T-cell lymphotropic virus 1 (HTLV-1) infection, including patients with ATLL; however, the correlation between H. pylori infection and ATLL gastric involvement has not been investigated. METHODS: The authors studied 71 patients with ATLL. Gastric involvement was confirmed by endoscopy and biopsy. H. pylori infection was detected by serology, rapid urease test, and immunohistochemistry on biopsy samples. The expression of adhesion molecules on ATLL cells or their ligands on the vasculature in gastric mucosa was analyzed immunohistochemically. The expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. RESULTS: Gastric involvement was detected in 21 patients (30%), including 8 patients with acute clinical subtype ATLL and 13 patients with lymphoma type ATLL. The prevalence of H. pylori infection was 86% (18 of 21 patients) in the patients with gastric involvement but only 38% (19 of 50 patients) in the patients without such involvement (P < 0.001). The expression of lymphocyte function-associated antigen 1 (LFA-1) and its ligand, intercellular adhesion molecule 1 (ICAM-1), was most frequent on ATLL cells infiltrating the stomach and was enhanced substantially on vascular endothelium in H. pylori-infected gastric mucosa. Human mucosal lymphocyte antigen 1 also was expressed on infiltrating ATLL cells in the stomach. The expression of MAdCAM-1 mRNA assessed by RT-PCR also was seen selectively in H. pylori-infected patients. CONCLUSIONS: ATLL cells infiltrate gastric tissues infected with H. pylori, probably through the interaction of adhesion molecules on these cells and their ligands on the vasculature, i.e., through the LFA-1/ICAM-1 pathway. Copyright 2002 American Cancer Society.
UI - 11920481
AU - Heerema NA; Sather HN; Sensel MG; La MK; Hutchinson RJ; Nachman JB;
TI - Reaman GH; Lange BJ; Steinherz PG; Bostrom BC; Gaynon PS; Uckun FM Abnormalities of chromosome bands 15q13-15 in childhood acute lymphoblastic leukemia.
SO - Cancer 2002 Feb 15;94(4):1102-10
AD - The Ohio State University Medical Center, Department of Pathology, Columbus, Ohio, USA. email@example.com
BACKGROUND: Recurring breakpoints in chromosome bands 15q13-15 occur infrequently in leukemia. To the authors' knowledge, the clinical significance of these breakpoints in childhood acute lymphoblastic leukemia (ALL) has not been previously investigated. METHODS: Centrally reviewed karyotypes of children with newly diagnosed ALL enrolled on Children's Cancer Group protocols from 1988 to 1995 formed the basis of the current report. Statistical analyses used chi-square tests for homogeneity of proportions, and outcome was analyzed using life table methods and associated statistics. RESULTS: Of 1946 cases with centrally reviewed and accepted cytogenetic analyses, 23 cases (1%) had breakpoints in chromosome bands 15q13-15. Most patients with 15q13-15 breakpoints had standard risk ALL, although breakpoints in 15q13-15 occurred more frequently in infants than in older children. The majority of these patients (16 patients; 70%) had balanced 15q13-15 rearrangements. Additional chromosomal abnormalities not involving 15q included abnormal 12p, abnormal 9p, Philadelphia chromosome, deletion 6q, and an 11q23 breakpoint. Thirteen (57%) 15q13-15 breakpoints occurred in pseudodiploid karyotypes; five (22%) were in hyperdiploid karyotypes with 47-50 chromosomes; two (9%) were in hyperdiploid karyotypes with > 50 chromosomes; and three (13%) were in hypodiploid karyotypes. Of the 23 patients with 15q13-15 breakpoints, 21 were survivors, 18 survived event-free for 2.2-9.3 years, and 3 were alive 1 to 3 years after a relapse at time of writing. CONCLUSIONS: The current study suggests that genes at 15q13-15 may be involved in the leukemogenesis of some cases of childhood ALL, but that with current intensive therapy such aberrations do not confer increased risk of treatment failure. Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10325
UI - 11807640
AU - de Haas V; Vet RJ; Verhagen OJ; Kroes W; van den Berg H; van der Schoot
TI - CE Early detection of central nervous system relapse by polymerase chain reaction in children with B-precursor acute lymphoblastic leukemia.
SO - Ann Hematol 2002 Jan;81(1):59-61
UI - 10049045
AU - Pongers-Willemse MJ; Seriu T; Stolz F; d'Aniello E; Gameiro P; Pisa P;
TI - Gonzalez M; Bartram CR; Panzer-Grumayer ER; Biondi A; San Miguel JF; van Dongen JJ Primers and protocols for standardized detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets: report of the BIOMED-1 CONCERTED ACTION: investigation of minimal residual disease in acute leukemia.
SO - Leukemia 1999 Jan;13(1):110-8
AD - Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, The Netherlands.
It is now widely accepted that the detection of minimal residual disease (MRD) has prognostic value in acute leukemia. However clinical MRD studies need standardized techniques. Therefore, several European laboratories have aligned their goals and performed comparative studies to achieve optimization and standardization of MRD techniques. This was achieved via the BIOMED-1 Concerted Action "Investigation of minimal residual disease in acute leukemia: International standardization and clinical evaluation." This report describes the development of PCR primers and protocols for the detection of MRD in acute lymphoblastic leukemia (ALL) using clone-specific junctional regions of immunoglobulin and T cell receptor gene rearrangements and TAL1 deletions as PCR targets. A total of 54 primers was developed (1) to amplify rearrangements of the TCRD, TCRG, and IGK (Kde) genes as well as TAL1 deletions; (2) to sequence the junctional regions and breakpoint fusion regions; and (3) to perform MRD detection in bone marrow or peripheral blood samples during follow-up of ALL patients. Protocols were established to identify PCR targets at diagnosis by performing 25 PCR reactions per patient using appropriate positive and negative controls. Standardized protocols were developed for MRD monitoring via single amplification of the PCR target followed by dot blot hybridization with the corresponding patient-specific junctional region probe. In addition, alternative approaches were designed for cases where the target sensitivity of at least 10(-4) was not obtained. The standardization described here of MRD-PCR techniques is essential for the process of translating MRD research into clinical practice.
UI - 10803512
AU - Porwit-MacDonald A; Bjorklund E; Lucio P; van Lochem EG; Mazur J;
TI - Parreira A; van den Beemd MW; van Wering ER; Baars E; Gaipa G; Biondi A; Ciudad J; van Dongen JJ; San Miguel JF; Orfao A BIOMED-1 concerted action report: flow cytometric characterization of CD7+ cell subsets in normal bone marrow as a basis for the diagnosis and follow-up of T cell acute lymphoblastic leukemia (T-ALL).
SO - Leukemia 2000 May;14(5):816-25
AD - Department of Pathology, Karolinska Hospital, Stockholm, Sweden.
The European BIOMED-1 Concerted Action was initiated in 1994 to improve and standardize the flow cytometric detection of minimal residual disease (MRD) in acute leukemia (AL). Three different protocols were defined to identify the normal subsets of B, T and myeloid cells in bone marrow (BM), and were applied to the different types of AL in order to study aberrant immunophenotypes. Using sensitive acquisition methods ('live gate') T cell subsets in normal BM could be identified with five triple-stains: CD7/CD5/CD3, CD7/CD4/CD8, CD7/CD2/CD3, CD7/CD38/CD34 and TdT/CD7/surface or cytoplasmic (cy)CD3 (antibodies conjugated with FITC/PE/PECy5 or PerCP, respectively). The identification of T cell subsets in BM allowed definition of 'empty spaces' (ie areas of flow cytometric plots where normally no cells are found). All studied T-ALL cases (n = 65) were located in 'empty spaces' and could be discriminated from normal T cells. The most informative triple staining was TdT/CD7/cyCD3, which was aberrant in 91% of T-ALL cases. In most cases, two or more aberrant patterns were found. Apparently the immunophenotypes of T-ALL differ significantly from normal BM T cells. This is mostly caused by their thymocytic origin, but also the neoplastic transformation might have affected antigen expression patterns. Application of the five proposed marker combinations in T-ALL contributes to standardized detection of MRD, since cells persistent or reappearing in the 'empty spaces' can be easily identified in follow-up BM samples during and after treatment.
UI - 10865981
AU - Delabesse E; Burtin ML; Millien C; Madonik A; Arnulf B; Beldjord K;
TI - Valensi F; Macintyre EA Rapid, multifluorescent TCRG Vgamma and Jgamma typing: application to T cell acute lymphoblastic leukemia and to the detection of minor clonal populations.
SO - Leukemia 2000 Jun;14(6):1143-52
AD - Biological Hematology, Hopital Necker-Enfants Malades and Universite Paris V, France.
Detection of clonal T cell receptor gamma (TCRG) gene rearrangements by PCR is widely used in both the diagnostic assessment of lymphoproliferative disorders and the follow-up of acute lymphoblastic leukaemia (ALL), when residual positivity in excess of 10(-3) at morphological complete remission is increasingly recognised to be an independent marker of poor prognosis. This is largely based on specific detection of V-J rearrangements from childhood cases. We describe rapid, multifluorescent Vgamma and Jgamma PCR typing of multiplex amplified diagnostic samples, as applied to 46 T-ALL. These strategies allow selected analysis of appropriate cases, immediate identification of Vgamma and Jgamma segments in over 95% of alleles, improved resolution and precision sizing and a sensitivity of detection at the 10(-2)-10(-3) level. We demonstrate preferential V-J combinations but no difference in V-J usage between children and adults, nor between SIL-TAL1-negative and -positive cases. A combination of fluorescent multiplex and Vgamma-Jgamma-specific monoplex follow-up, as described here, will allow detection of both significant clonal evolution and of the diagnostic clone at a level of prognostic significance, by techniques which can readily be applied to large-scale prospective studies for which real-time analysis is required.
UI - 10914544
AU - Szczepanski T; Langerak AW; Willemse MJ; Wolvers-Tettero IL; van Wering
TI - ER; van Dongen JJ T cell receptor gamma (TCRG) gene rearrangements in T cell acute lymphoblastic leukemia refelct 'end-stage' recombinations: implications for minimal residual disease monitoring.
SO - Leukemia 2000 Jul;14(7):1208-14
AD - Department of Immunology, University Hospital Rotterdam/Erasmus University Rotterdam, The Netherlands.
The T cell receptor gamma (TCRG) gene configuration was established in a large series of 126 T cell acute lymphoblastic leukemia (T-ALL) patients using combined Southern blotting (SB) and heteroduplex PCR analyses. The vast majority of TALL (96%) displayed clonal TCRG gene rearrangements, with biallelic recombination in 91% of patients. A small immature subgroup of CD3- T-ALL (n = 5) had both TCRG genes in germline configuration, three of them having also germline TCRD genes. In five patients (4%) combined SB and PCR results indicated oligoclonality. In five rearrangements detected by SB, the Vgamma gene segment could not be identified suggesting illegitimate recombination. Altogether, 83% of TCRG gene rearrangements involved either the most upstream Vgamma2 gene (including four cases with interstitial deletion of 170 bp in Vgamma2) and/or the most downstream Jgamma2.3 segment, which can be perceived as 'end-stage' recombinations. Comparative analysis of the TCRG gene configuration in the major immunophenotypic subgroups indicated that TCRgammadelta+ T-ALL display a less mature immunogenotype as compared to TCRalphabeta+ and most CD3- cases. This was reflected by a significantly increased usage of the more downstream Vgamma genes and the upstream Jgamma1 segments. Comparison between adult and pediatric T-ALL patients did not show any obvious differences in TCRG gene configuration. The high frequency, easy detectability, rare oligoclonality, and frequent 'end-stage' recombinations make TCRG gene rearrangements principal targets for PCR-based detection of minimal residual disease (MRD) in T-ALL. We propose a simple heteroduplex PCR strategy, applying five primer combinations, which results in the detection of approximately 95% of all clonal TCRG gene rearrangements in T-ALL. This approach enables identification of at least one TCRG target for MRD monitoring in 95% of patients, and even two targets in 84% of T-ALL.
UI - 11480575
AU - van Wering ER; van der Linden-Schrever BE; van der Velden VH;
TI - Szczepanski T; van Dongen JJ T-lymphocytes in bone marrow samples of children with acute lymphoblastic leukemia during and after chemotherapy might hamper PCR-based minimal residual disease studies.
SO - Leukemia 2001 Aug;15(8):1301-3
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 - 10673739
AU - Kaleem Z; Shuster JJ; Carroll AJ; Borowitz MJ; Pullen DJ; Camitta BM;
TI - Zutter MM; Watson MS Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group Study.
SO - Leukemia 2000 Feb;14(2):238-40
AD - Division of Surgical Pathology, Washington University School of Medicine, St Louis, MO, USA.
We present the clinicopathologic findings and survival data on 10 patients with acute lymphoblastic leukemia (ALL) and a rare t(8;14)(q11.2;q32). There were five male and five female patients, nine Caucasians and one Black, aged 4-17 (median 10.9) years. Three had Down syndrome. Eight (80%) patients had a white blood cell (WBC) count <50 x 109/l at presentation. No patient had central nervous system involvement or a mediastinal mass. Two patients had concurrent splenomegaly and hepatomegaly. Adenopathy was absent in four, minimal in three, moderate in one and prominent in two patients. All eight cases where immunophenotyping was performed by flow cytometry showed a B-precursor phenotype with expression of CD10 (CALLA). Only one case exhibited t(8;14)(q11.2;q32) as the sole karyotypic abnormality. Three patients were classified as standard-risk and seven high-risk by NCI (National Cancer Institute) consensus risk group categories. All patients achieved complete remission and seven patients were in complete continuous remission (CCR) after chemotherapy designed for B-precursor ALL. Three patients relapsed after 23.5, 31.3 and 32.1 months of EFS; the first patient also had t(9;22)(q34;q11), the second had a WBC count of 126 x 109/l at presentation while the third patient had no high risk features except for age 10 years. Thus, from our data, the t(8;14)(q11.2;q32) does not appear to confer an increased risk of relapse. Further observations are needed to confirm this conclusion.
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 - 11915569
AU - Vilmer E; Dhedin N
TI - [Acute lymphoblastic leukemia]
SO - Rev Prat 2002 Jan 15;52(2):213-7
AD - Service d'hemato-immunologie pediatrique, hopital Robert-Debre, APHP, 75019 Paris.
UI - 7812006
AU - Madsen PS; Hokland P; Clausen N; Ellegaard J; Hokland M
TI - Differential expression levels of the heat shock protein 27 isoforms in pediatric normal, nonleukemic and common acute lymphoblastic leukemia B-cell precursors.
SO - Blood 1995 Jan 15;85(2):510-21
AD - University Department of Medicine and Hematology, Aarhus Amtssygehus, Denmark.
Heat shock protein 27 (hsp27) may function as a regulator of microfilament dynamics and may participate in signal transduction pathways of different cell growth regulators, with the mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 being a major enzyme responsible for its phosphorylation. Using two-dimensional gel electrophoresis, we have compared the expression levels of two hsp27 isoelectric variants (hsp27 isoforms) M2 (molecular weight, 26 kD; isoelectric point, 6.02) and M3 (molecular weight, 26 kD; isoelectric point, 5.60) in pediatric bone marrow CD19+CD10+B-cell precursors (BCPs) purified from either common acute lymphoblastic leukemia (c-ALL) patients, normal donors, or non-c-ALL patients. Compared with normal BCPs, we found increased hsp27 expressions (M2 isoform) (by a factor 5 to 9 of mean level) in c-ALL as well as in non-c-ALL (nonleukemic) precursors. Though increased phosphorylation of hsp27 (M3 isoform) was observed in BCPs from c-ALL patients at relapse (by a factor 3 of mean level compared with normal BCPs and precursors from c-ALL at diagnosis), which might represent a differential enzymatic activity, this was not distinguishable from that of non-c-ALL patients. Therefore, our studies suggest constitutive differences of hsp27 isoforms between pediatric leukemic BCPs and their relatively low-expressing, immunophenotypically normal bone marrow counterparts. In light of the occasional and possibly transient increase of hsp27 expression during nonleukemic BCP differentiation and the possible role of hsp27 in signal transduction to microfilaments, these differences might be of considerable biologic interest and of importance in future studies of regulated normal or dysregulated leukemic hematopoietic cellular differentiation.
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 - 9573029
AU - Tanaka Y; Mine S; Figdor CG; Wake A; Hirano H; Tsukada J; Aso M; Fujii
TI - K; Saito K; van Kooyk Y; Eto S Constitutive chemokine production results in activation of leukocyte function-associated antigen-1 on adult T-cell leukemia cells.
SO - Blood 1998 May 15;91(10):3909-19
AD - The First Department of Internal Medicine , University of Occupational and Environmental Health, Japan.
Adult T-cell leukemia (ATL) is characterized by massive infiltration of circulating ATL cells into a variety of tissues, a finding often associated with poor prognosis. Leukocyte migration from circulation into tissue depends on integrin-mediated adhesion to endothelium, and integrins are tightly regulated by several stimuli, such as inflammatory chemokines. However, the exact mechanisms that enhance adherence of leukemic cells to the endothelium and infiltration into tissues remain to be fully understood. We investigated the mechanisms of extravasation of leukemic cells using ATL cells and report the following novel features of endogenous chemokine-induced adhesion of ATL cells to the endothelium. ATL cells spontaneously adhered to endothelial cells without exogenous stimulation. Integrin leukocyte function-associated antigen-1 (LFA-1) on ATL cells was spontaneously activated. ATL cells produced high amounts of chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha), and MIP-1beta. Adhesion of ATL cells to endothelial cells and the expression of activated form of LFA-1 were reduced by pretreatment with pertussis toxin, wortmannin, or anti-MIP-1alpha and MIP-1beta antibodies or transfection with antisense of MIP-1alpha or MIP-1beta. Spontaneous polymerization of cytoskeletal F-actin was observed in ATL cells, which was also inhibited by pertussis toxin and wortmannin. We propose that ATL cells adhere to endothelial cells through an adhesion cascade similar to normal leukocytes and that the chemokines produced by ATL cells are involved in triggering integrin LFA-1 through cytoskeletal rearrangement induced by G-protein-dependent activation of phosphoinositide 3-kinases in an autocrine manner. These events result in a strong adhesion of ATL cells to the endothelium and spontaneous transendothelial migration.
UI - 10079288
AU - Thorpe KL; Schafer AJ; Genin E; Trowsdale J; Beck S
TI - Detection of polymorphism in the RING3 gene by high-throughput fluorescent SSCP analysis.
SO - Immunogenetics 1999 Apr;49(4):256-65
AD - The Sanger Centre, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
We describe the use of a high-throughput, fluorescent, polymorphism-detection system, based on single-strand conformation polymorphism to screen for polymorphism in the RING3 gene. This is the first extensive mutation screen of this major histocompatibility complex-linked gene, and the entire coding region and intron-exon junctions were examined by multiplexing over 3000 polymerase chain reaction products. These techniques should be applicable for analysis of variation in other human genes. Investigation of DNA from acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) patients, as well as healthy individuals revealed low levels of polymorphism across the RING3 gene. Comparison of the distribution of genotypes at each polymorphic site between patients and healthy individuals revealed a single site which significantly deviates from Hardy-Weinberg proportions.
UI - 10500837
AU - Matheson EC; Hall AG
TI - Expression of DNA mismatch repair proteins in acute lymphoblastic leukaemia and normal bone marrow.
SO - Adv Exp Med Biol 1999;457():579-83
AD - LRF Molecular Pharmacology Group, CRU, Medical School, Newcastle-Upon-Tyne.
Errors during normal DNA synthesis may produce mismatched base pairs. 6-Mercaptopurine (6MP), given during continuing therapy in acute lymphoblastic leukaemia (ALL), undergoes intracellular activation to give cytotoxic thioguanine nucleotides which are then incorporated into the DNA of dividing cells in place of guanine. Cell death is thought to result from futile attempts at mismatch repair. Previous work has shown that cell lines with a defect in this pathway develop tolerance to incorporated 6-thioguanine bases. In order to investigate the possible relevance of mismatch repair to the chemosensitivty of blasts to 6MP, relative to normal tissues, we have measured the expression of the mismatch repair proteins MLH1, MSH2, PMS2 and MSH6 in blasts from children and adults with ALL and in normal bone marrows, using western blotting. Fifty cases of childhood ALL, 22 cases of adult ALL and 7 normal marrows have been studied. Expression of MSH2, and of MLH1 in all but three cases, was detectable in all the blasts studied. Noticeably, expression of MLH1 was not detected in any of the normal marrow samples. MSH2 was detected in 4 of the normal marrows. Expression of PMS2 was not detected in 29 cases of ALL and, like MLH1, was absent from each of the normal marrow samples. In contrast, MSH6 was detected in all of the normal marrows and all but 16 of the cases of ALL. There was no difference in expression between adults and children. These results may help to explain the relative sensitivity of leukaemic blasts to thiopurines at presentation as compared to normal bone marrow.
UI - 11406533
AU - Cazzaniga G; Daniotti M; Tosi S; Giudici G; Aloisi A; Pogliani E;
TI - Kearney L; Biondi A The paired box domain gene PAX5 is fused to ETV6/TEL in an acute lymphoblastic leukemia case.
SO - Cancer Res 2001 Jun 15;61(12):4666-70
AD - Clinica Pediatrica, Universita di Milano-Bicocca, Ospedale San Gerardo, 20052 Monza, Italy.
The PAX5 gene, encoding the B-cell-specific activator protein, is a critical determinant of commitment to the B-lymphocyte pathway. This gene, mapped at 9p13, is juxtaposed to the immunoglobulin heavy chain (IgH) gene as a result of the t(9;14)(p13;q32), a rare but recurring translocation found in a subset of B-cell non-Hodgkin's lymphoma cases. In all of these, this translocation results in deregulated expression of the gene product because of the proximity of IgH. We present here the molecular characterization of a previously reported acute lymphoblastic leukemia case carrying a t(9;12)(q11;p13) translocation. Using 5' rapid amplification of cDNA ends PCR, a novel chimeric transcript was identified that contained the NH(2)-terminal region of PAX5 and most of the ETV6/TEL gene on 12p13. According to the fusion transcript, the resulting chimeric protein would retain the PAX5 paired-box domain and both the helix-loop-helix and DNA binding domains of TEL. Thus, it is reasonable to hypothesize that this protein could act as an aberrant transcription factor. This is the first report of PAX5 rearrangement in a human malignancy resulting in a chimeric transcript.
UI - 11886378
AU - Konig M; Reichel M; Marschalek R; Haas OA; Strehl S
TI - A highly specific and sensitive fluorescence in situ hybridization assay for the detection of t(4;11)(q21;q23) and concurrent submicroscopic deletions in acute leukaemias.
SO - Br J Haematol 2002 Mar;116(4):758-64
AD - Children's Cancer Research Institute (CCRI), St. Anna Kinderspital, Vienna, Austria.
The translocation t(4;11)(q21;q23) is one of the most frequent 11q23 abnormalities associated with infant leukaemia as well as topoisomerase inhibitor-induced secondary leukaemias. On the molecular level, the MLL gene on 11q23 is fused to the AF4 gene in the 4q21 region, resulting in a chimaeric MLL/AF4 fusion transcript. These particular chromosome rearrangements are generally considered to be associated with poor prognosis, and therefore accurate detection at diagnosis is of clinical significance. In this study we developed a highly specific dual-colour fluorescence in situ hybridization (FISH) assay for the detection of the t(4;11) and demonstrate its usefulness for interphase molecular cytogenetics. In our approach, differentially labelled genomic clones that span the breakpoint cluster regions of both genes involved in the specific translocation were used. Thus, t(4;11)-positive nuclei will display two fusion signals and for t(4;11) cases with concurrent 3' MLL deletions only one fusion signal will be displayed. A very low false-positive value of less than 0.1% was obtained for interphase cells with two fusion signals. In contrast, in cases with 3' MLL deletions that display only one fusion signal, the rate of false-positive nuclei was 10.4%. This FISH assay enables the screening of larger series of patients with haematological diseases for t(4;11) translocations and allows the unambiguous detection of associated cryptic deletions.
UI - 11902302
AU - Meshinchi S; Thomson B; Finn L S; Leisenring W; Green C; Radich J P;
TI - Loken M; Hawkins D Comparison of multidimensional flow cytometry with standard morphology for evaluation of early marrow response in pediatric acute lymphoblastic leukemia.
SO - J Pediatr Hematol Oncol 2001 Dec;23(9):585-90
AD - Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA. email@example.com
PURPOSE: We compared multidimensional flow cytometry (MDF) with morphology in evaluating early marrow response to induction chemotherapy in pediatric ALL. METHODS: Chemotherapy response was determined by standard morphology or by MDF assessed by residual leukemic cell percentage remaining in the marrow on days 7, 14, and 28 of induction. Bone marrow response was classified as M3 (>25% leukemic blasts) or M1/M2 (< or = 25% leukemic blasts). Multidimensional flow cytometry evaluation was compared with that of standard morphology. Available day-7 and day-14 marrow slides were also reevaluated by a single pathologist without patients' clinical information. RESULTS: Of 46 day-7 specimens, eight (17%) had discordant MDF and morphologic results (P < 0.001), including six classified as M3 by morphology but were M1/M2 by MDF, and two were classified as M3 by MDF but were M1/M2 by morphology. Of 24 day-14 bone marrow specimens, five (20.5%) were discordant (P < 0.001), including two classified as M3 by morphology but were M1/M2 by MDF, and three were classified as M3 by MDF but were M1/M2 by morphology. Reevaluation of the blinded day-7 and day-14 marrow slides yielded discordance between repeated pathology readings of 11% (P < 0.001) and 6% (P = 0.04), respectively. CONCLUSION: Our data show significant discordance between the morphologic and MDF evaluation of early marrow response. Early response to therapy is a significant prognostic indicator in pediatric acute lymphoblastic leukemia and is used to alter subsequent treatment; thus, precise assessment of response is important. A larger comparison of MDF with morphology for the evaluation of early response, including correlation with clinical outcome, is warranted.
UI - 11843292
AU - Tsuchiya T; Hagihara M; Shimakura Y; Ueda Y; Gansuvd B; Munkhbat B;
TI - Inoue H; Tazume K; Kato S; Hotta T The generation of immunocompetent dendritic cells from CD34+ acute myeloid or lymphoid leukemia cells.
SO - Int J Hematol 2002 Jan;75(1):55-62
AD - Department of Hematology and Rheumatology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
The ability of CD34+ leukemic cells to differentiate to dendritic cells (DCs) was investigated in 18 acute myeloid leukemia (AML) and 4 lymphoid leukemia (ALL) patients. The generation of DCs was determined by the expression of DC-associated CD1a or CD83 (more than 30%) with costimulatory molecules, by CD80 antigens (>20%), and by the exhibition of allostimulatory activity. In the AML patients, allostimulatory mature DCs were generated from 3 of 9 M0 or M1, 2 of 5 M2,2 of 4 M4 or M5, and 3 of 4 ALL (L2) cases. In total, DCs were more efficiently induced from cases expressing over 75% of CD34+ among whole bone marrow mononuclear cells (8 of 12), compared with those under 75% (2 of 10; P < .05). B-cell (CD19), natural killer (NK)-cell (CD56), or T-cell (CD7) lineage markers, which were aberrantly expressed on the blasts, were rarely found on leukemic DCs at the end of the culture period, and myeloid (CD13, CD33), not lymphoid (CD10), markers were shown on ALL-derived DCs. In Philadelphia chromosome-positive ALL or AML patients with t (8;21), DCs were confirmed to be of leukemic origin by fluorescence in situ hybridization analysis.
UI - 11823363
AU - Greaves M
TI - Childhood leukaemia.
SO - BMJ 2002 Feb 2;324(7332):283-7
AD - Leukaemia Research Fund Centre, Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB. firstname.lastname@example.org
UI - 11830473
AU - Nyvold C; Madsen HO; Ryder LP; Seyfarth J; Svejgaard A; Clausen N;
TI - Wesenberg F; Jonsson OG; Forestier E; Schmiegelow K; The Nordic Society for Pediatric Hematology and Oncology Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome.
SO - Blood 2002 Feb 15;99(4):1253-8
AD - Department of Clinical Immunology and Department of Pediatrics, National University Hospital, Rigshospitalet, Copenhagen, Denmark.
The postinduction level of minimal residual disease (MRD) was quantified with a competitive polymerase chain reaction (PCR) technique in 104 children with acute lymphoblastic leukemia (ALL) diagnosed between June significant correlation was found between the MRD level on day 15 (D15) and day 29 (D29) after the start of induction therapy (r(s) = 0.70, P <.0001). The 15 patients with T-cell disease had higher D29 MRD than those with B-lineage ALL (P =.01). Age was positively related to D29 MRD (r(s) = 0.32, P =.001). The 16 patients who had a relapse had higher D15 and D29 MRD levels than the patients who stayed in remission (median levels D15, 1% versus 0.1%, P =.03; D29, 0.4% versus 0.01%, P =.0001). No patients with a MRD level less than 0.01% on D29 have so far had a relapse, whereas the 7-year probability of event-free survival for patients with higher MRD levels was 0.52 (P =.0007). The group of patients with a D29 MRD less than 0.01% included patients with T-cell disease, white blood cell count more than 50 x 10(9)/L at diagnosis, or age 10 years or older, and could not be identified by up-front criteria. The best-fit Cox model to predict the risk of relapse included D29 MRD (P =.004) and age (P =.009). These findings indicate that with the present treatment protocol MRD quantification at an early stage of therapy identifies patients with a very low risk of relapse. Further trials are needed to reveal whether such patients with D29 MRD less than 0.01% can be cured with less intensive chemotherapy, which would reduce the risk of serious late effects as well as the costs of therapy.
UI - 11830485
AU - Mori N; Sato H; Hayashibara T; Senba M; Hayashi T; Yamada Y; Kamihira S;
TI - Ikeda S; Yamasaki Y; Morikawa S; Tomonaga M; Geleziunas R; Yamamoto N Human T-cell leukemia virus type I Tax transactivates the matrix metalloproteinase-9 gene: potential r