National Cancer Institute®
Last Modified: February 1, 2002
UI - 11340522
AU - Viscoli C; Paesmans M; Sanz M; Castagnola E; Klastersky J; Martino P;
TI - Glauser M; International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer Association between antifungal prophylaxis and rate of documented bacteremia in febrile neutropenic cancer patients.
SO - Clin Infect Dis 2001 Jun 1;32(11):1532-7
AD - University of Genova and National Institute for Cancer Research, Genova, Italy. firstname.lastname@example.org
Published data have suggested a correlation between antifungal prophylaxis and bacteremia in febrile neutropenia. This correlation was investigated among 3002 febrile neutropenic patients enrolled in 4 trials during 1986-1994. Globally, 1322 patients (44%) did not receive antifungal prophylaxis; 835 (28%) received poorly absorbable antifungal agents and 845 (28%) received absorbable antifungal agents. The rates of bacteremia for these groups were 20%, 26%, and 27%, respectively (P=.0001). In a multivariate model without including antifungal prophylaxis, factors associated with bacteremia were: age, duration of hospitalization, duration of neutropenia before enrollment, underlying disease, presence of an intravenous catheter, shock, antibacterial prophylaxis, temperature, and granulocyte count at onset of fever. When antifungal prophylaxis was included, the adjustment quality of the model improved slightly (P=.05), with an odds ratio of 1.19 (95% confidence interval [CI], 0.92-1.55) for patients receiving nonabsorbable and 1.42 (95% CI, 1.07-1.88) for those who were receiving absorbable antifungal agents. Antifungal prophylaxis with absorbable agents might have an impact on the rate of documented bacteremia in febrile neutropenia. This effect should be confirmed prospectively.
UI - 11527155
AU - Hensel JP; Gillert E; Fey GH; Marschalek R
TI - Breakpoints of t(4;11) translocations in the human MLL and AF4 genes in ALL patients are preferentially clustered outside of high-affinity matrix attachment regions.
SO - J Cell Biochem 2001;82(2):299-309
AD - University of Erlangen-Nurnberg, Erlangen, Germany.
Chromosomal translocations t(4;11) are based on illegitimate recombinations between the human MLL and AF4 genes, and are associated with high-risk acute leukemias of infants and young children. Here, the question was asked, whether a correlation exists between the location of translocation breakpoints within both genes and the location of S/MARs. In "halo mapping experiments" (to define SARs), about 20 kb of MLL DNA was found to be attached to the nuclear matrix. Similar experiments performed for the translocation partner gene AF4 revealed that SARs are spanning nearly the complete breakpoint cluster region of the AF4 gene. By using short DNA fragments in "scaffold reassociation experiments" (to define MARs), similar results were obtained for both genes. However, Distamycin A competition experiments in combination with "scaffold reassociation experiments" revealed specific differences in the affinity of each tested DNA fragment to bind the isolated nuclear matrix proteins. When the latter data were compared with the known location of chromosomal breakpoints for both genes, an unexpected correlation was observed. DNA areas with strong MAR affinity contained fewer translocation breakpoints, while areas with weak or absent MAR affinity showed a higher density of chromosomal breakpoints.
UI - 11697624
AU - Baghdassarian N; Bertrand Y; Gerland LM; Ffrench P; Duhaut P; Bryon PA;
TI - Magaud JP; Ffrench M Bcl-2, cell cycle regulatory proteins and corticosensitivity in childhood acute lymphoblastic leukaemia.
SO - Leuk Lymphoma 2001 Sep-Oct;42(5):1067-75
AD - Laboratoire de Cytologie Analytique, Universite Claude Bernard, Unite INSERM U453, Lyon, France.
The results of treatment in childhood acute lymphoblastic leukemia (ALL) remain incompletely satisfactory because of relapses observed even with high dose chemotherapy. The aim of this study was to evaluate the role of bcl-2 or cell cycle regulatory protein expression in peripheral blood cells before and during the first 48 hours of corticotherapy, and corticosensitivity criteria for predicting relapse and prognosis. Fifty two children presenting with ALL were studied at diagnosis and during the first 48 hours of treatment for the level of cell proliferation by measurement of DNA content, and for expression of several cell proliferation regulatory proteins by Western blot. Two criteria for corticosensitivity were used: 1--the number of blast cells present after seven days of treatment with a threshold at 1 G/L (usual criterion), 2--the D8/D1 blast cell ratio, which is independent of the initial leucocytosis. Relapse in the total patient population or in B-cell ALL could only be predicted by the level of leucocytosis before treatment or by p27kip1 expression during the first 48 hours of treatment. Disease free survival was significantly longer when the D8/D1 blast cell ratio was under the 0.75 quartile in the entire patient population (p = 0.03). Among the proteins analyzed, bcl-2 expression before treatment and p27kip1 expression analyzed after 48 hours of corticotherapy were the sole variables associated with significant differences in disease free survival duration in the entire patient population (p < 0.01 and p = 0.04 respectively) or in the B-cell ALL subgroup (p < 0.01). Comparable results were obtained for the overall survival data. The significance of these results is discussed but such a study on blood blast cells needs to be validated in a larger series.
UI - 11697628
AU - Hofmann WK; Tsukasaki K; Takeuchi N; Takeuchi S; Koeffler HP
TI - Methylation analysis of cell cycle control genes in adult T-cell leukemia/lymphoma.
SO - Leuk Lymphoma 2001 Sep-Oct;42(5):1107-9
AD - Division of Hematology/Oncology, Cedars-Sinai Research Institute, UCLA School of Medicine, Los Angeles, California 90048, USA.
Central to many cancers is the aberrant expression of genes that regulate the cell cycle including the cyclin-dependent kinase inhibitors known as p15INK4b and p16INK4a, p14ARF and the retinoblastoma (RB) protein. We performed a detailed analysis of the methylation status of these genes by methylation specific polymerase chain reaction (MSP) in tumor cells of 35 adult T-cell leukemia/lymphoma (ATL) patients. We found in nine of 35 cases (26%) at least one gene methylated. The frequency of p15INK4b methylation was 7 of 35 (20%). The incidence of methylation of p14ARF and p16INK4a was two of 35 (6%) and one of 35 (3%), respectively. The RB gene was not found to be methylated in any of the ATL samples. The data indicate that inactivation of these cell cycle regulatory genes by hypermethylation is important in the development of ATL.
UI - 11809679
AU - Whiteside D; McLeod R; Graham G; Steckley JL; Booth K; Somerville MJ;
TI - Andrew SE A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots.
SO - Cancer Res 2002 Jan 15;62(2):359-62
AD - Department of Medical Genetics, University of Alberta, Edmonton, Alberta, T6G 2H7 Canada.
Individuals with a germ-line mutation in one of the DNA mismatch repair (MMR) genes are at significant risk for colorectal cancer and other tumors. Three families have previously been reported with individuals homozygous for mutations in the MMR gene MLH1 that are predicted to compromise MMR. These individuals develop hematological malignancies and/or neurofibromatosis type 1 at an early age. Here, in an individual, we demonstrate that a homozygous novel mutation in the MMR gene MSH2 is associated with leukemia and multiple cafe-au-lait spots, a feature of neurofibromatosis type 1. Because the hematological malignancies observed in the individuals homozygous for the loss of MMR are reflective of the lymphomas seen in mice lacking MMR, the mice may provide a useful model for human neoplasia.
UI - 11426548
AU - Arima N; Tei C
TI - HTLV-I Tax related dysfunction of cell cycle regulators and oncogenesis of adult T cell leukemia.
SO - Leuk Lymphoma 2001 Jan;40(3-4):267-78
AD - First Department Internal Medicine, Faculty of Medicine, Kagoshima University, Japan. email@example.com
HTLV-I is causually related to the oncogenesis of adult T cell leukemia (ATL). However, the precise mechanism of HTLV-I oncogenesis is unclear. HTLV-I Tax protein functions as an activator of various cellular genes, including IL-2, IL-2 receptor-alpha, and c-fos through the activation of nuclear transfer factors such as NF-kappaB and SRF, and also potently activates trascription of viral genes through CREB/ATF sites in the viral LTR. However, Tax activation of HTLV-I infected T cells through the above pathways induces polyclonal proliferation of the cells in vitro; Tax however may function only transiently in the immediate post-infection period following infection in vivo. The long latent period of 60 years from infection to onset of disease suggests other mechanisms for ATL oncogenesis. Recent studies suggest that the malignant transformation of ATL is a multi-hit phenomena, suggesting that discrete genetic events are responsible for ATL oncogenesis. These genetic events could be responsible for the different stages of ATL: smoldering, chronic, lymphoma, and acute type, p16 and p53 genes are important negative regulators of the cell cycle and are often found to be mutated in neoplasms. Recent studies including ours demonstrated a high frequency of alteration of these two genes in primary ATL cells. Furthermore, alteration of the two genes is associated with acute but not chronic type ATL. In addition, p16 gene alteration is linked to the growth rate of ATL cells, suggesting that the alteration of these cell cycle regulatory genes may be related to progression from smoldering or chronic to acute or lymphoma type ATL. Tax may be involved in mutagenesis of these genes through suppression of DNA-beta polymerase gene expression during the process from latent period to acute/lymphoma type. Once transformation occurs, activation of the pathway between Tax and the three nuclear transfer factors, NF-kappaB, SRF, and CREB/ATF, contributes to establish the aggressive manifestations of acute/lymphoma type ATL cells.
UI - 11426549
AU - Uckun FM; Gaynon PS; Stram DO; Sensel MG; Sarquis MB; Willoughby M
TI - Bone marrow leukemic progenitor cell content in pediatric T-lineage acute lymphoblastic leukemia patients with an isolated extramedullary first relapse.
SO - Leuk Lymphoma 2001 Jan;40(3-4):279-85
AD - ALL Biology Reference Laboratory, Parker Hughes Cancer Center, Parker Hughes Institute, St. Paul, MN 55113, USA.
Isolated extramedullary relapse in childhood acute lymphoblastic leukemia (ALL) is associated frequently with the T-lineage immunophenotype and may be accompanied by occult bone marrow disease. We employed highly sensitive multiparameter flow cytometry and blast colony assays to quantify the leukemic progenitor cell (LPC) burden in the pretreatment bone marrows of 15 pediatric T-lineage ALL patients with an isolated extramedullary first relapse. Sites of extramedullary relapse were CNS (11 patients), testes (3 patients), and both CNS and testes (1 patient). Bone marrow LPC were detectable in 8 patients (53%) and undetectable in 7 patients (47%) at day 0 of post-relapse induction therapy, with LPC counts ranging from 0/10(6) mononuclear cells (MNC) to 518/10(6) MNC (mean +/- SEM, 50+/-34/10(6) MNC). Five of 9 patients with an early relapse (< 18 months after achieving a first complete remission [CR1]) and 3 of 6 patients with a late relapse (> or = 18 months from CR1) had detectable bone marrow LPC at day 0. Five of 8 patients with NCI-defined poor risk ALL and 3 of 7 patients with NCI-defined standard risk ALL had detectable LPC at day 0. Following post-relapse induction chemotherapy. LPC counts were detectable in bone marrows of 4 of 6 evaluated patients. Thus, approximately half of the extramedullary relapse T-lineage ALL patients studied had substantial occult involvement of the bone marrow. These findings may partly explain the previously observed poor prognosis of T-lineage patients following a CNS relapse.
UI - 11426564
AU - Einsiedel HG; Taube T; Beyermann B; Dragon S; Moricke A;
TI - Kebelmann-Betzig C; Kochling J; Henze G; Seeger K Absence of mutations in the CDKN2 binding site of CDK4 in childhood acute lymphoblastic leukemia.
SO - Leuk Lymphoma 2001 Jan;40(3-4):413-7
AD - Department of Pediatric Oncology/Hematology, Charite Campus Virchow Klinikum, Humboldt-University Berlin, Germany.
The cell cycle regulatory circuit resulting in phosphorylation of the retinoblastoma protein (pRB) is frequently altered in human cancers. Several mechanisms of disruption are known in that pathway. In childhood acute lymphoblastic leukemia (ALL), the main disrupting mechanism is the homozygous deletion of the CDKN2 (cyclin dependent kinase inhibitor 2) genes: p16CDKN2a, p15CDKN2b, and p19ARF. Another pRB pathway disturbance is a previously described point mutation in the exon 2 of CDK4, a pRB phosphorylating enzyme, which abrogates binding of the latter to its inhibitors, p16CDKN2a and p15CDKN2b. Here we report the absence of point mutations in the CDKN2-binding site of CDK4 in 100 cases of childhood ALL, 2 cases of childhood chronic myeloid leukemia and 9 hematologic cell lines screened by PCR-SSCP (polymerase chain reaction single stranded conformational polymorphism gel electrophoresis), thereby minimizing the possibility of the existence of these specific CDK4 mutations in childhood ALL.
UI - 11680831
AU - Lex C; Korholz D; Kohlmuller B; Bonig H; Willers R; Kramm CM; Gobel U
TI - Infectious complications in children with acute lymphoblastic leukemia and T-cell lymphoma--a rationale for tailored supportive care.
SO - Support Care Cancer 2001 Oct;9(7):514-21
AD - Department of Pediatric Hematology and Oncology, Children's Hospital, Heinrich Heine University of Dusseldorf, Germany.
Infections still remain a major cause of therapy-associated morbidity and death in patients with malignant diseases. To further lower the risk of serious and long-lasting infections by additional supportive measures, detailed information on the frequency and characteristic features of infections is needed. Therefore, patient data from 112 children with acute lymphoblastic leukemia and T-cell lymphoma who were treated according to the COALL-05-92 protocol in our department were analyzed for differences in the frequency and origin of febrile episodes in relation to age, immunological type of leukemia, treatment in group assessed as being at high or low risk of relapse, actual occurrence of relapse, and course of chemotherapy. At the time of diagnosis, low-risk patients more commonly presented with febrile episodes than high-risk patients. In total, patients developed a fever in 313 (24%) of 1,307 evaluated chemotherapy cycles. Febrile episodes were associated with microbiologically or clinically documented infections in 60% of all cases, while in 40% the fever was of unknown origin. Gram-positive pathogens had a markedly higher incidence than gram-negative or fungal ones. The incidence of febrile episodes during therapy appeared to be correlated with certain chemotherapeutic drug combinations. The highest rate was found after high-dose cytarabine and asparaginase causing a long period of leukopenia. However, after other chemotherapy courses with a similar duration of leukopenia the incidence of febrile episodes was significantly lower, suggesting that specific interactions of different chemotherapeutic agents with the immune response might be an important factor in development of infections. Individual factors might also account for an increased incidence of infections, since the number of high-risk patients with recurrent infections was significantly higher than expected on the basis of statistical evaluation. In conclusion, our findings suggest that the risk of infections during chemotherapy may not only be influenced by leukopenia, but that drug-specific effects of the various chemotherapeutic agents and individual factors may also be important contributory factors. These observations must be further expanded in prospective studies so that new tailored supportive care protocols can be elaborated.
UI - 11705851
AU - Koomagi R; Zintl F; Sauerbrey A; Volm M
TI - Vascular endothelial growth factor in newly diagnosed and recurrent childhood acute lymphoblastic leukemia as measured by real-time quantitative polymerase chain reaction.
SO - Clin Cancer Res 2001 Nov;7(11):3381-4
AD - Department of Oncological Diagnostics and Therapy, German Cancer Research Center, In Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
PURPOSE: Overexpression of vascular endothelial growth factor (VEGF) is associated with increased angiogenesis, growth, and metastasis in solid tumors, but to date the significance of VEGF in leukemia has received only limited attention. Therefore, this study examined the cellular VEGF levels in 31 newly diagnosed and 22 recurrent cases of childhood acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: VEGF was determined with real-time quantitative PCR methods. Kaplan-Meier statistical analyses were conducted for the relapse-free intervals and the overall survival times. The groups were compared by log-rank and rank-sum tests. RESULTS: The VEGF levels were significantly higher in recurrent ALL compared with newly diagnosed ALL (28.0 versus 3.1 units; P = 0.001). Kaplan-Meier estimates were conducted to analyze the prognostic value of VEGF levels in newly diagnosed ALL with regard to the relapse-free intervals and the overall survival times. In this analysis, the median relapse-free interval of patients with low VEGF levels was more than 10 years, whereas the relapse-free interval of patients with high VEGF expression was only 1.2 years. The median overall survival time for the collective with low VEGF levels was >10 years, whereas the survival of the group of patients with high VEGF levels was 3.9 years. This difference was not statistically significant. This may be attributable to the small number of patients involved. CONCLUSION: Our data suggest that VEGF may play an important role in the pathophysiology of ALL. The expression of VEGF raises the possibility of using angiogenesis inhibitors as a novel therapeutic strategy in childhood ALL.
UI - 11705857
AU - Whetstine JR; Gifford AJ; Witt T; Liu XY; Flatley RM; Norris M; Haber M;
TI - Taub JW; Ravindranath Y; Matherly LH Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers.
SO - Clin Cancer Res 2001 Nov;7(11):3416-22
AD - Department of Pharmacology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, 110 East Warren Avenue, Detroit, MI 48201, USA.
The presence of sequence variants in the human reduced folate carrier (hRFC) was assessed in leukemia blasts from children with acute lymphoblastic leukemia (ALL) and in normal peripheral blood specimens. A CATG frame shift insertion at position 191 was detected in 10-60% of hRFC transcripts from 10 of 16 ALL specimens, by RFLP analysis and direct sequencing of hRFC cDNAs. In genomic DNAs prepared from 105 leukemia (n = 54) and non-leukemia (n = 51) specimens, PCR amplifications and direct sequencing of exon 3 identified a high-frequency G to A single nucleotide polymorphism at position 80 that resulted in a change of arginine-27 to histidine-27. The allelic frequencies of G/A80 were nearly identical for the non-leukemia (42.2% CGC and 57.8% CAC) and leukemia (40.7% CGC and 59.3% CAC) genomic DNAs. In cDNAs prepared from 10 of these ALL patients, identical allelic frequencies (40 and 60%, respectively) were recorded. In up to 62 genomic DNAs, hRFC-coding exons 4-7 were PCR-amplified and sequenced. A high-abundance C/T696 polymorphism was detected with nearly identical frequencies for both alleles, and a heterozygous C/A1242 sequence variant was identified in two ALL specimens. Both C/T696 and C/A1242 were phenotypically silent. In transport assays with [(3)H]methotrexate and [(3)H]5-formyl tetrahydrofolate, nearly identical uptake rates were measured for the arginine-27- and histidine-27-hRFC proteins expressed in transport-impaired K562 cells. Although there were no significant differences between the kinetic parameters for methotrexate transport for the hRFC forms, minor (approximately 2-fold) differences were measured in the K(i)s for other substrates including Tomudex, 5,10-dideazatetrahydrofolate, GW1843U89, and 10-ethyl-10-deazaaminopterin and for 5-formyl tetrahydrofolate.
UI - 11237064
AU - Tabernero MD; Bortoluci AM; Alaejos I; Lopez-Berges MC; Rasillo A;
TI - Garcia-Sanz R; Garcia M; Sayagues JM; Gonzalez M; Mateo G; San Miguel JF; Orfao A Adult precursor B-ALL with BCR/ABL gene rearrangements displays a unique immunophenotype based on the pattern of CD10, CD34, CD13 and CD38 expresssion.
SO - Leukemia 2001 Mar;15(3):406-14
AD - Departamento de Medicina, and Centro de Investigaciones del Cancer, University of Salamanca, Spain.
The Philadelphia chromosome (Ph+) reflects a balanced reciprocal translocation between the long arms of chromosomes 9 and 22 [t(9;22)(q34;q11.2] involving the BCR and ABL genes. At present, detection of BCR/ABL gene rearrangements is mandatory in precursor-B-ALL patients at diagnosis for prognostic stratification and treatment decision. In spite of the clinical impact, no screening method, displaying a high sensitive and specificity, is available for the identification of BCR/ABL+ precursor-B-ALL cases. The aim of the present study was to explore the immunophenotypic characteristics of precursor B-ALL cases displaying BCR/ABL gene rearrangements using multiple stainings analyzed by quantitative flow cytometry in order to rapidly (<1 h) identify unique phenotypes associated with this translocation. From the 82 precursor-B-ALL cases included in the study 12 displayed BCR/ABL gene rearragements, all corresponding to adult patients, four of which also displayed DNA aneuploidy. Our results show that BCR/ABL+ precursor B-ALL cases constantly displayed a homogeneous expression of CD10 and CD34 but low and relatively heterogeneous CD38 expression, together with an aberrant reactivity for CD13. In contrast, this unique phenotype was only detected in three out of 70 BCR/ABL cases. Therefore, the combined use of staining patterns for CD34, CD38 and CD13 expression within CD10-positive blast cells is highly suggestive of BCR/ABL gene rearrangements in adults with precursor B-ALL.
UI - 11587205
AU - Bernard OA; Busson-LeConiat M; Ballerini P; Mauchauffe M; Della Valle V;
TI - Monni R; Nguyen Khac F; Mercher T; Penard-Lacronique V; Pasturaud P; Gressin L; Heilig R; Daniel MT; Lessard M; Berger R A new recurrent and specific cryptic translocation, t(5;14)(q35;q32), is associated with expression of the Hox11L2 gene in T acute lymphoblastic leukemia.
SO - Leukemia 2001 Oct;15(10):1495-504
AD - U434 INSERM-CEPH and SD401 No. 434 CNRS, Paris, France.
FISH identified a cryptic t(5;14)(q35;q32) in T acute lymphoblastic leukemia (ALL), whereas it was not observed in B ALL samples. This translocation is present in five out of 23 (22%) children and adolescents with T ALL tested. RanBP17, a gene coding for a member of the importin beta protein family, and Hox11Like2, an orphan homeobox gene were mapped close to the chromosome 5 breakpoints and CTIP2, which is highly expressed during normal T cell differentiation, was localized in the vicinity of the chromosome 14 breakpoints. The Hox11L2 gene was found to be transcriptionally activated as a result of the translocation, probably under the influence of CTIP2 transcriptional regulation elements. These data establish the t(5;14)(q35;q32) as a major abnormality, and Hox11 family member activation as an important pathway in T ALL leukemogenesis.
UI - 11587210
AU - Moreira I; Papaioannou M; Mortuza FY; Gameiro P; Palmisano GL; Harrison
TI - CJ; Prentice HG; Mehta AB; Hoffbrand AV; Foroni L Heterogeneity of VH-JH gene rearrangement patterns: an insight into the biology of B cell precursor ALL.
SO - Leukemia 2001 Oct;15(10):1527-36
AD - Haematology Department, Royal Free and University College School of Medicine, London, UK.
Oligoclonal B cell proliferation, as defined by the presence of more than one leukemic clone, has been detected in approximately 20% to 30% of patients with acute lymphoblastic leukemia (ALL) using PCR or Southern blotting. An accurate assessment of these populations is required to avoid false negative measurements of minimal residual disease (MRD) in follow-up bone marrow (BM) samples of ALL patients. In this study, we analysed 29 ALL patients with two or more immunoglobulin heavy (IGH) chain gene rearrangements in the presentation samples using IGH fingerprinting PCR and sequence analysis. Thirty-nine (51%) of 76 sequences (from 15 patients), shared no VNDNJ homology (ie different CDR3 regions). In the remaining 14 patients, at least two related VH sequences were identified in each patient (identical DNJ sequences). Numerical abnormalities of chromosome 14 was detected in 10 patients. Eight patients were analysed at presentation and relapse. In four of them, expansion of a minor presentation-clone was detected at relapse while the major presentation clone disappeared, confirming 'subclonal evolution'. Finally, in our cohort of patients, the presence of related or unrelated IGH clones did not influence overall survival.
UI - 11587218
AU - Blair A; Rowbottom AW; Browne SJ; Goulden NJ; Steward CG; Oakhill A;
TI - Pamphilon DH An optimised biphasic culture system for the generation of functional dendritic cells from patients with acute lymphoblastic leukaemia at presentation and in clinical remission.
SO - Leukemia 2001 Oct;15(10):1596-603
AD - Bristol Institute for Transfusion Sciences and Royal Hospital for Sick Children, UK.
We have tested the hypothesis that functional dendritic cells (DC) may be generated from patients with acute lymphoblastic leukaemia (ALL). We evaluated the production of DC from blast cells taken at presentation from nine children with ALL. Blast cells were expanded in serum-free medium supplemented with Flt3L, G-CSF, GM-CSF, IL-3, IL-6 and SCF for 7 days and subsequently stimulated with Flt3L, GM-CSF and TGF-beta for a further 14 days, with the addition of TNF-alpha for the final 48 h of culture. Cultured cells had the morphological appearance of DC and expressed the DC-associated antigens CD1A (range 2-87%) and CD83 (15-44%). Expression of the co-stimulatory molecules CD80 and CD86 was increased and the majority of these cells retained their expression of CD34 (73+/-4%) and HLA-DR (79+/-5%). Seven of the nine ALL had a leukaemia-specific abnormality and DC generated from five of these seven cases were derived from the leukaemic clone. Leukaemic DC derived from four HLA-A*02-positive ALL pulsed with CMV-associated peptides could induce significant proliferation of peptide-specific CD8+ T cells. This specificity was verified using tetrameric complexes of HLA class l/antigenic peptide. DC could also be generated from cells taken at times of complete remission of ALL and from normal controls using these culture conditions. These findings show that functional DC can be generated both from ALL blasts and from patients in remission; these might be utilised in future for immunotherapeutic strategies in the treatment of ALL.
UI - 11801311
AU - Yehuda-Gafni O; Cividalli G; Abrahmov A; Weintrob M; Neriah SB; Cohen R;
TI - Abeliovich D Fluorescence in situ hybridization analysis of the cryptic t(12;21) (p13;q22) in childhood B-lineage acute lymphoblastic leukemia.
SO - Cancer Genet Cytogenet 2002 Jan 1;132(1):61-4
AD - Department of Human Genetics, Hadassah Hebrew University Hospital and Medical School, Jerusalem 91120, Israel.
We evaluated retrospectively the cryptic t(12;21)(p13;q22) in 15 children with early B-lineage acute lymphocytic leukemia who had a normal karyotype by using the locus specific probes of TEL and AML1 genes in a dual color fluorescence in situ hybridization (FISH). The FISH analysis revealed six patients with the fusion gene TEL/AML1 on chromosome 21, three of whom possessed a double fusion gene. In addition, the AML1 probe revealed hyperdiploid clones that were not detected in the conventional cytogenetic analysis. A discrepancy between the proportion of cells with the fusion gene in interphase nuclei and metaphases was noted.
UI - 11801312
AU - Paz-y-Mino C; Burgos R; Morillo SA; Santos JC; Fiallo BF; Leone PE
TI - BCR-ABL rearrangement frequencies in chronic myeloid leukemia and acute lymphoblastic leukemia in Ecuador, South America.
SO - Cancer Genet Cytogenet 2002 Jan 1;132(1):65-7
AD - Laboratorio de Genetica Molecular y Citogenetica Humana, Departamento de Ciencias Biologicas, Pontificia Universidad Catolica del Ecuador, P.O. Box 17-1-2184, Quito, Ecuador. firstname.lastname@example.org
Different BCR-ABL transcript variants occur more or less frequently, according to the leukemia type. We report the frequencies of BCR-ABL transcript variants studied in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) patients in the Ecuadorian population. The frequencies found for CML patients in this study were 94.6% for the b2/a2 rearrangement and 5.4% for the b3/a2 rearrangement; whereas in ALL, all cases (100%) that presented the BCR-ABL rearrangement had the e1/a2 junction. Since our results differ from the frequencies previously reported, we suggest that this may be due to a different genetic background in the population involved in this study when compared to the populations analyzed in prior studies. Furthermore, we recommend a survey of the BCR-ABL transcript variants and their frequencies in different ethnic groups.
UI - 11801318
AU - Zamora L; Espinet B; Sole F; Salido M; Rodon N; Florensa L; Woessner S
TI - Translocation (5;17)(q13;q21) in a case with precursor T-lymphoblastic lymphoma/leukemia.
SO - Cancer Genet Cytogenet 2002 Jan 1;132(1):81-2
UI - 11853794
AU - Hofmann WK; de Vos S; Elashoff D; Gschaidmeier H; Hoelzer D; Koeffler
TI - HP; Ottmann OG Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study.
SO - Lancet 2002 Feb 9;359(9305):481-6
AD - Division of Haematology and Oncology, Cedars Sinai Research Institute, UCLA School of Medicine, Los Angeles, CA, USA. W.K.Hoffman@em.uni-frankfurt.de
BACKGROUND: The ABL tyrosine kinase inhibitor STI571 is a promising agent for treatment of advanced Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia. However, resistance to this drug develops within a few months in most patients. We aimed to predict resistance to STI571. METHODS: Total RNA was extracted from 25 bone-marrow samples from 19 patients with Ph+ acute lymphoblastic leukaemia who were enrolled into a phase II study. 17 samples were obtained before STI571 treatment was started: ten from individuals who were classified as good responders to STI571 (sensitive), and seven from individuals who did not to respond to STI571 (primary resistance). Eight samples were obtained from patients during treatment with STI571. We analysed six matched samples, which were obtained before and during treatment with STI571. Oligonucleotide microarray analysis of samples was done with high-density microarrays. FINDINGS: We identified 95 genes whose expression could be used to predict sensitivity of leukaemic cells to STI571. On this basis, all the STI571-sensitive samples could clearly be distinguished from the resistant cases. 56 highly differentially expressed genes were identified in leukaemic cells that were secondarily resistant to STI571. Resistant leukaemic cells expressed high levels of Bruton's tyrosine kinase and two ATP synthetases (ATP5A1 and ATP5C1), and showed significantly reduced expression of the proapoptotic gene BAK1 and the cell-cycle control gene p15 INK4b. INTERPRETATION: We have shown the clinical relevance of gene expression data for the pretreatment assessment of acute lymphoblastic leukaemia. Our results have implications for future clinical studies of tyrosine kinase inhibitors.
UI - 11721412
AU - Chen W; Zhang W; Zhu J
TI - [Homozygous deletion and methylation of p16 and p15 gene in acute leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Sep;20(9):474-6
AD - Beijing Red-cross Chaoyang Hospital, Capital University of Medical Sciences, Beijing 100020.
OBJECTIVE: To investigate the frequency of p16 and p15 gene inactivation in acute leukemia and to evaluate its clinical significance. METHODS: Fifty-six patients with newly diagnosed acute leukemia was studied. PCR technique was used to detect homozygous deletion of p16 and p15 gene, restriction enzyme-PCR technique was used to detect gene methylation, and TdT-mediated dUTP-digoxygenin end-labeling (TUNEL) technique was used to detect cell apoptosis. RESULTS: p16 and/or p15 gene inactivation was detected in 33 of the 56 patients, including 23/38 (60.5%) of the ALL patients (T-ALL 12/16, B-ALL 11/22) and 10/18 (55.5%) of the ANLL patients. For All patients, methylation was the major pathway of p16 and p15 gene inactivation. Patients with p16 and/or p15 gene inactivation had a delayed apoptosis, a poor response to chemotherapy, a lower remission rate and a shortened remission duration. CONCLUSION: The inactivation of p16 and p15 gene plays a key role in the pathogenesis of acute leukemia.
UI - 11863221
AU - Onciu M; Lai R; Vega F; Bueso-Ramos C; Medeiros LJ
TI - Precursor T-cell acute lymphoblastic leukemia in adults: age-related immunophenotypic, cytogenetic, and molecular subsets.
SO - Am J Clin Pathol 2002 Feb;117(2):252-8
AD - Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
We analyzed the clinicopathologic and molecular findings in 26 adults (age 16-72 years) with T-cell acute lymphoblastic leukemia (T-ALL) and observed features that correlated with age. Patients older than 60 years (n = 5) had a low frequency of hepatosplenomegaly (0 [0%]), anterior mediastinal mass (1 [20%]), and lymphadenopathy (2 [40%]), and completely responded to chemotherapy (4 of 4). The T-ALL in this group commonly expressed myeloid antigens (4 [80%]), had lineage-inappropriate gene rearrangements (2/3 [67%]) and chromosome 2 deletion (3/4 [75%]), and exclusively used the V(III) or V(IV) families of the T-cell receptor (TCR) gamma gene. In comparison, patients 16 to 60 years old (n = 21) more commonly had an anterior mediastinal mass (8 [38%]), hepatosplenomegaly (10 [48%]), and lymphadenopathy (16 [76%]). The tumors in these patients commonly used the TCR gamma gene VI or V(II) families (17/25 total rearrangements [68%]). Myeloid antigen expression (5 [24%]) and lineage inappropriate gene rearrangements (4/15 [27%]) were uncommon. Within this group, CD1a expression correlated with age 28 to 60 years. These results illustrate considerable age-related heterogeneity in adult T-ALL, which may reflect differences in tumor cell maturation.
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