National Cancer Institute®
Last Modified: November 21, 2001
UI - 21402012
AU - Cabrera ME; Campbell M; Quintana J; Undurraga MS; Ford AA; Greaves MF
TI - [Clinical significance and frequency of the 11q23/MLL genetic molecular alteration in Chilean infants with acute leukemia]
SO - Rev Med Chil 2001 Jun;129(6):634-42
AD - Departamento de Medicina, Campus Oriente, Facultad de Medicina Universidad de Chile. firstname.lastname@example.org
BACKGROUND: Acute leukemia (AL) in infants generally shows distinctive biologic features and has a poor prognosis. AIM: To study the frequency of the cytogenetic alteration of 11q23 chromosome or the recombination of MLL gene in infants less than 18 months old, with acute leukemia. PATIENTS AND METHODS: We analyzed 37 cases of AL in infants less than 18 months of age diagnosed in Chile from 1989 to 1999. The clinical features and cytogenetic/molecular defects of 11q23MLL gene rearrangement and their influence in prognosis were determined. RESULTS: There were 18 cases of acute Lymphoblastic leukemia (ALL) characterized by female sex (67%) high presenting leukocyte count (median 99 x 109/L), blast cells with a CD10 negative phenotype (50%) and 11q23/MLL rearrangement (39%). Molecular abnormalities of 11q23 were significantly associated with adverse prognosis, with an event free survival (EFS) of only 14 +/- 12%. Interestingly, infants with germ line 11q23 had a very good outcome with an EFS of 73 +/- 11% (p < 0.025). There were 19 cases of acute myeloblastic leukemia (AML) characterized by male sex (63%) high leukocyte count (median 93 x 109/L), FAB-MS morphology (53%) and 11q23/MLL rearrangement (53%). EFS was very poor, 20 +/- 9% and 33 +/- 4% for rearranged and germinal group respectively (p = NS), due to a high mortality rate during the first month of diagnosis. CONCLUSIONS: These findings demonstrate that Chilean ALL infants with 11q23 abnormalities have a very poor prognosis. However those with germinal state can enjoy a prolonged disease free survival with the current treatment protocols.
UI - 21450469
AU - Smith A; Robson L; Heaps LS; Sharma P; Dunlop L; Bhave A; Bradstock K
TI - Routine fluorescence in situ hybridization with the MLL probe does not reliably detect two separate signals on one chromosome 11 in patients with trisomy 11.
SO - Cancer Genet Cytogenet 2001 Sep;129(2):173-6
AD - Department of Cytogenetics, Royal Alexandra Hospital for Children, Locked Bag 4001, NSW 2145, Westmead, Australia. email@example.com
Trisomy 11 is considered to be a rare cytogenetic abnormality in myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). Duplication of the MLL gene (localized to 11q23) has been found on one chromosome 11 in patients with trisomy 11, detected by DNA techniques. We investigated copy number of MLL in seven patients with trisomy 11 to see if duplication could be assessed by the detection of two separate signals on fluorescence in situ hybridization (FISH). If so, FISH could provide a quick easy screen of MLL status in routine referrals. The diagnostic bone marrow aspirate showed trisomy 11 in five adult patients with MDS/AML as part of a complex karyotype and in two children with acute lymphoblastic leukemia (ALL) as part of a hyperdiploid karyotype. Fluorescence in situ hybridization utilized the suspensions remaining after the cytogenetic harvest. Two FISH probes were used on the adult patients (MLL - Oncor and Vysis), and one (Vysis) for the two children with ALL. Analysis showed that the proximity of the two putative hybridization signals made it very difficult to unambiguously see two separate signals. The hybridisations (Oncor probe) were convincing of MLL duplication (namely two distinct signals) in only one patient, but this was not borne out with the other MLL probe (Vysis). We conclude that conventional FISH with MLL probe is not suited to act as a screen for MLL duplication in patients with trisomy 11.
UI - 21390867
AU - Chen H; Sun G; Han R
TI - [In vitro study on the effects of the novel retinoids combined with IFN-gamma on the proliferation and differentiation of fresh acute monocytic leukemic cells]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Jan;20(1):10-3
AD - Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025.
OBJECTIVE: To investigate the prospect for clinical use of novel retinoids YS 904012 and R 9158 in combination with IFN-gamma in inducing differentiation of acute monocytic leukemia. METHODS: The effects of novel retinoids with IFN-gamma on the differentiation and clonal proliferation of fresh leukemia cell from 6 monocytic leukemia patients were studied in vitro. Cell morphological examination, nitro tetrazolium blue reduction test and DCE, expression of CD14 and CD68 and CFU-L were used in the study. RESULTS: The primary leukemia cell, cultured with the combination of YS 904012 and IFN-gamma, became more mature in morphology. The NBT reduction rate and DCE were increased from 23.4% and 25.0% to 61.5% and 52.0%, respectively. The expression of CD14 and CD68 was increased. The growth of the leukemic colony in semi-solid culture was markedly inhibited. The activity of YS 904012 combined with IFN-gamma in inhibiting proliferation and inducing differentiation of monoblast was greater than that of R9158 or all-trans retinoic acid in combination with IFN-gamma (P < 0.01). CONCLUSION: The YS 904012 combined with IFN-gamma is worthy of further study for clinical differentiation therapy of acute monocytic leukemia.
UI - 21390870
AU - Hua D; Li J; Xia X
TI - [The clinical and biological significance of megakaryocytic antigen expression in acute myeloid leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Jan;20(1):21-3
AD - First Affiliated Hospital of Suzhou Medical College, Suzhou 215006.
OBJECTIVE: To explore megakaryocytic (MK) antigen expression in previously untreated adult acute myeloid leukemia (AML) and its relation to the clinical and biological characteristics. METHODS: Two hundred and eleven cases of AML were detected with flow cytometric immunofluorescence assay. RESULTS: Twenty-seven cases (12.8%) were MK antigen positive with the higher positive rates in hybrid acute leukemia (45.5%) and acute monoblastic leukemia (24.1%). MK antigen expression was significantly correlated with CD34 antigen expression, high white cell count, high P-glycoprotein positivity and had no correlation with chromosome aberration. 33.3% of MK positive AML patients achieved complete remission which was significantly lower than that (71.9%) in MK negative cases. CONCLUSION: MK antigen positive AML might derived from malignant transformation of hemotopoietic stem cell at earlier stage and the detection of MK expression was of values in predicting treatment effect and prognosis for adult AML.
UI - 21329582
AU - Benoit GR; Flexor M; Besancon F; Altucci L; Rossin A; Hillion J;
TI - Balajthy Z; Legres L; Segal-Bendirdjian E; Gronemeyer H; Lanotte M Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.
SO - Mol Endocrinol 2001 Jul;15(7):1154-69
AD - INSERM U-496, Centre G. Hayem Hopital Saint-Louis 75010 Paris, France.
On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.
UI - 21341701
AU - Goto Y; Yue L; Yokoi A; Nishimura R; Uehara T; Koizumi S; Saikawa Y
TI - A novel single-nucleotide polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene with enhanced expression.
SO - Clin Cancer Res 2001 Jul;7(7):1952-6
AD - Department of Pediatrics, Kanazawa University School of Medicine, Kanazawa, Ishikawa 920-8641, Japan.
A novel single-nucleotide polymorphism (SNP), 829C-->T in the 3'-untranslated region of the human dihydrofolate reductase (DHFR) gene transcript, was identified in the study population of 37 patients with childhood leukemias/lymphomas and 83 healthy Japanese children. Frequencies of the DHFR 829C/C, 829C/T, and 829T/T genotypes were 83.8, 10.8, and 5.4%, respectively, in the cases and 74.7, 19.3, and 6.0% in the controls, showing no significant difference in genotype frequencies between the cases and controls. When determined by real-time quantitative reverse transcription-PCR analysis, the highest expression of the DHFR transcript was demonstrated in the samples with a DHFR 829T/T polymorphism (P < 0.001). Direct association of the presence of the SNP with methotrexate-related adverse events in each patient was not demonstrated in this limited analysis. These data suggest that the novel DHFR 829 polymorphism is associated with a positive role in gene expression and provide evidence of a functional SNP in the 3' regulatory region of the gene.
UI - 21371226
AU - Tan H; Ying H; Chu J
TI - [Augmented effect of Composite Radix Salviae Miltiorrhizae Injection on radiosensitivity of leukemia cells]
SO - Zhongguo Zhong Xi Yi Jie He Za Zhi 1998 May;18(5):279-81
AD - Second Affiliated Hospital, Guangzhou Medical College, Guangzhou 510260.
OBJECTIVE: To explore the effect of Composite Radix Salviae Miltiorrhizae Injection (CSMI) on radiosensitivity of leukemia cells. METHODS: Semisolid agar culture and flow cytometry assay were performed for studying the change in radiosensitivity of HL60 cell line and fresh human leukemia cells after exposing to CSMI. RESULTS: The D0(the inverse of the slope of the survival curve) and SF2(survival fraction at 2 Gy) of HL60 cell line were decreased from 1.53, 0.34 to 0.93, 0.12, respectively and apoptosis rates after radiation were raised significantly by CSMI. Furthermore, the concentration of CSMI and the time of mixed culture with CSMI before irradiation had positive relation to the effects mentioned above. Compared with control group, CSMI could increase the radiation-induced apoptosis of fresh leukemia cells (5.89 +/- 2.91% vs 12.05 +/- 3.06%). CONCLUSION: CSMI could obviously enhance the radiosensitivity of leukemia cells.
UI - 21424592
AU - Kilian PH; Skrzypek S; Becker N; Havemann K
TI - Exposure to armament wastes and leukemia: a case-control study within a cluster of AML and CML in Germany.
SO - Leuk Res 2001 Oct;25(10):839-45
AD - Department of Haematology, Marburg University Medical Center, Baldingerstrasse, 35033, Marburg, Germany.
An unusually high incidence of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) concentrated in a specific locality of a region in Germany motivated a descriptive incidence study in that region which showed a near 10-fold increased risk of CML among males but not among females (Kolb G, Becker N, Scheller S, Zugmaier G, Pralle H, Wahrendorf J, Havemann K. Increased risk of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in a County of Hesse, Germany, Soc Prev Med 1993;38:190-195). Since a serious environmental contamination of areas in this locality with armament wastes containing toluene-derivatives has been known for a long time, the hypothesis arose that TNT production and the related severe contamination of soil and water might be responsible for the observed higher risk. We carried out a case-control study within the cluster to test this hypothesis. Overall, the results do not confirm the hypothesis. There is an indication of a relationship of an increased odds ratio with the exposure for a small group of persons who lived at a particular site in one of the two communities involved during the peak phase of TNT production during the 1940s. However, this finding is spurious and cannot explain the large majority of cases which occurred in that area in the 1980s. At the moment, no other explanation can be given for the increased risk of leukemias in that area.
UI - 21424603
AU - Dodge JE; Munson C; List AF
TI - KG-1 and KG-1a model the p15 CpG island methylation observed in acute myeloid leukemia patients.
SO - Leuk Res 2001 Oct;25(10):917-25
AD - Department of Pharmacology and Toxicology, University of Arizona, Arizona Cancer Center, Tucson, AZ 85724-5024, USA. firstname.lastname@example.org
p15 and p16 are tumor suppressor genes that have 5' CpG islands and both are subject to hypermethylation associated with their transcriptional inactivation in hematological malignancies. In this study, we used sodium bisulfite sequencing to obtain a complete map of the 5-methylcytosine status of 80 CpGs covering approximately 900 bp in the 5' p15 CpG island, and 53 CpGs covering approximately 700 bp in the 5' p16 CpG island in the hematopoietic cell lines HL60, KG-1, and KG-1a, two normal human bone marrow samples (NBM), and eight cytosine arabinoside (ara-C)-resistant adult acute myeloid leukemia (AML) patients. We found methylation of the p15 CpG island in 75% of the AML cases studied spread throughout the 5' region analyzed but only minimal methylation of p15 in NBM. Further, the p16 CpG island was not aberrantly methylated in NBM or the eight AML patients studied. Two distinct modes of p15 methylation in AML were identified, variegated and complete. Interestingly, KG-1 and KG-1a model the methylation of p15 observed in AML, where KG-1 methylation is variegated and KG-1a methylation is complete. Both KG-1 and KG-1a had no detectable p15 mRNA or protein. These results demonstrate that rather than continuous increases in p15 methylation, surprisingly two punctuated modes of aberrant p15 methylation, variegated and complete, were observed in vitro and in vivo. Thus aberrant methylation of tumor suppressor genes is not a binary switch but in the case of p15 occurs in two independent and stable states.
UI - 21329982
AU - Watanabe M; Kohri M; Takaishi M; Horie R; Higashihara M
TI - Molecular cloning and sequencing of myosin light chains in human megakaryoblastic leukemia cells.
SO - J Smooth Muscle Res 2001 Feb;37(1):25-38
AD - Fourth Department of Internal Medicine, School of Medicine, Kitasato University, Sagamihara-shi, Kanagawa, Japan.
Myosin light chain genes of hematopoietic cells have yet to be characterized. We cloned the full-length cDNAs of 20 kDa regulatory myosin light chain (MLC-2) and 17 kDa essential myosin light chain (MLC-3) from Meg-01, a human megakaryoblastic leukemia cell line. Both MLC-2 and MLC-3 gene are transcribed ubiquitously in various hematopoietic cells. The MLC-2 open reading frame of 516 nucleotides encoding a protein of 172 residues was detected in cloned cDNA of 967 nucleotides. The Ca2+-binding domain and five phosphorylation sites were highly conserved. The deduced amino acid sequence has a 99.4% and 100% homology with that of human fetus brain and human lymphocyte, respectively. The MLC-3 open reading frame of 453 nucleotides encoding a protein of 151 residues was detected in cloned cDNA of 742 nucleotide. The MLC-3 protein is 99.3% identical to that of human fibroblasts. These results suggest that hematopoietic myosin light chain proteins are similar to those of other nonmuscle cells and smooth muscle, thus differing from skeletal and cardiac muscles.
UI - 21519129
AU - Alcalay M; Orleth A; Sebastiani C; Meani N; Chiaradonna F; Casciari C;
TI - Sciurpi MT; Gelmetti V; Riganelli D; Minucci S; Fagioli M; Pelicci PG Common themes in the pathogenesis of acute myeloid leukemia.
SO - Oncogene 2001 Sep 10;20(40):5680-94
AD - Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy. email@example.com
The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of specific chromosome translocations. Of the two components of each fusion protein, one is generally a transcription factor, whereas the other partner is more variable in function, but often involved in the control of cell survival and apoptosis. As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid differentiation, determine a stage-specific arrest of maturation and enhance cell survival in a cell-type specific manner. The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant co-repressor complexes, alterations in chromatin remodeling, and disruption of specific subnuclear compartments. The identification and analysis of common and specific target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-specific drug design.
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