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National Cancer Institute®
Ultima Vez Modificado: 1 de enero del 2002
UI - 11200370
AU - Persson L; Vikerfors T; Sjoberg L; Engervall P; Tidefelt U
TI - Increased incidence of bacteraemia due to viridans streptococci in an unselected population of patients with acute myeloid leukaemia.
SO - Scand J Infect Dis 2000;32(6):615-21
AD - Department of Infectious Diseases, Orebro Medical Centre Hospital, Sweden.
The aetiology, clinical characteristics and outcome of bacteraemia in patients with acute myeloid leukaemia were studied. All positive blood cultures collected at a haematological ward during 2 7-y periods were evaluated. Altogether, 274 episodes of bacteraemia in 152 patients were recorded, 80 episodes during 1980-86 and 194 during 1990-96. During the 2 periods, trimethoprim-sulfamethoxazol in combination with amikacin was the first-line empirical therapy in patients with neutropaenia and fever. In 1990, antimicrobial prophylaxis with ciprofloxacin and fluconazole was introduced. The incidence of bacteraemia due to viridans streptococci or coagulase-negative staphylococci increased from the first period to the second, whereas the incidence of Enterobacteriaceae decreased. In granulocytopaenic patients during 1990-96, viridans streptococci accounted for 21% of the isolates and in patients treated prophylactically with fluoroquinolone, viridans streptococci accounted for 31%. All viridans streptococci were sensitive to penicillin. At the time of the positive blood cultures, the patients of the second period were granulocytopaenic in 83% of the episodes. The mortality related to septicaemia during the later period was 13% and only 1 of 33 (3%) of the patients with viridans streptococci died. Eight patients (9%) died in relation to septicaemia following curative antileukaemic therapy.
UI - 11442494
AU - Mustjoki S; Alitalo R; Elonen E; Carpen O; Gahmberg CG; Vaheri A
TI - Intercellular adhesion molecule-1 in extravasation of normal mononuclear and leukaemia cells.
SO - Br J Haematol 2001 Jun;113(4):989-1000
AD - Departments of Virology, University of Helsinki, Finland. Satu.Mustjoki@helsinki.fi
Interaction of intercellular adhesion molecules (ICAMs) with their receptors has a key role in normal leucocyte adhesion and migration, whereas in leukaemia this has not been well established. In this study, we have evaluated the roles of different adhesion molecules in normal and leukaemia cell extravasation in a novel organotypic model for vessel wall and measured plasma ICAM-1 and -2 levels in acute leukaemia patients at diagnosis and during chemotherapy. We found that both normal mononuclear cells and blast cells from acute leukaemia patients, as well as retinoic acid-treated promyelocytic leukaemia cells, rapidly extravasated through endothelial cell layers into the underlying collagen matrix. ICAM-1 antibody prevented the extravasation, while antibodies to other adhesion molecules showed little (CD18, ICAM-2) or no inhibition (CD11a and ICAM-3). Soluble ICAM-1 (sICAM-1) protein had no effect. We also observed increased plasma sICAM-1 and -2 levels in leukaemia patients and found that they correlated only weakly with the white blood cell count. No correlation was found between sICAM-1 or -2 levels and the response to therapy. Although elevated sICAM-2 levels decreased rapidly during chemotherapy, sICAM-1 levels did not. Because sICAM-1 protein had no effect on leukaemia cell extravasation in vitro, it is probable that the increased plasma sICAM-1 levels in leukaemia patients may not play a role in leukaemia cell infiltration. However, as we showed that ICAM-1 mediated leukaemia cell extravasation on the cell surface, it is possible that cellular ICAM-1 has an important role in disease progression.
UI - 11550287
AU - Inokuchi K; Hamaguchi H; Taniwaki M; Yamaguchi H; Tanosaki S; Dan K
TI - Establishment of a cell line with AML1-MTG8, TP53, and TP73 abnormalities from acute myelogenous leukemia.
SO - Genes Chromosomes Cancer 2001 Oct;32(2):182-7
AD - Division of Hematology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113, Japan. email@example.com
Gene alterations accumulate during the progression of acute myelogenous leukemia (AML) to a malignant clone. Here, a new myeloid cell line, designated YSK-21, with the balanced t(8;21)(q22;q22) and the unbalanced der(1)t(1;17)(p36;q21), was established. YSK-21 grows well in a medium containing recombinant human granulocyte colony-stimulating factor (rhG-CSF), granulocyte-macrophage colony-stimulating factor (rhGM-CSF), or interleukin-3 (rhIL-3). Molecular analysis using the reverse transcriptase-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) revealed that t(8;21)(q22;q22) resulted in an AML1-MTG8 fusion transcript. FISH and spectral karyotyping (SKY) in conjunction with G-banding analysis revealed a der(1)t(1;17)(p36;q21) chromosomal translocation, which appeared in the clone developed from the original leukemic cells. Molecular analysis of the TP73 gene on 1p36 and the TP53 gene revealed a deletion of one-allele in TP73 with partial demethylation of another allele in the initial clone of YSK, and a point mutation consisting of an A-->T substitution in codon 288 of the TP53 gene in the developed clone of YSK-21. YSK-21 cells, expressing aberrant AML1-MTG8, TP53, and TP73 protein molecules, may be useful for elucidating the pathophysiology of these aberrant proteins and for studying the der(1)t(1;17)(p36;q21) chromosomal translocation. Copyright 2001 Wiley-Liss, Inc.
UI - 11564070
AU - Rigolin GM; Della Porta M; Bigoni R; Tieghi A; Cuneo A; Castoldi G
TI - Dendritic cells in acute promyelocytic leukaemia.
SO - Br J Haematol 2001 Sep;114(4):830-3
AD - Section of Haematology, Department of Biomedical Sciences, University of Ferrara, Corso Giovecca, 203, 44100 Ferrara, Italy. firstname.lastname@example.org
Dendritic cell (DC) differentiation was investigated in samples from two acute promyelocytic leukaemia (APL) patients with classic translocation t(15;17)(q22;q21). After 18 d of culture in the presence of granulocyte-macrophage colony-stimulating factor, interleukin 4 and tumour necrosis factor alpha, 10-15% of pathological promyelocytes had differentiated into DC-like cells, as demonstrated by immunological and functional characteristics and by analysis of CD1a+ cells. In one patient, analysed at relapse and after developing a picture of secondary myelodysplastic syndrome (MDS), three different populations of DCs were demonstrated, two of which derived from pathological myeloid precursors (the APL and the MDS clones). This patient's DCs also presented abnormal dextran uptake. Our results demonstrated that pathological myeloid precursors in APL can differentiate into DC-like elements and that different populations of pathological DCs may coexist in the same patient.
UI - 11568009
AU - Zunino R; Li Q; Rose SD; Romero-Benitez MM; Lejen T; Brandan NC; Trifaro
TI - JM Expression of scinderin in megakaryoblastic leukemia cells induces differentiation, maturation, and apoptosis with release of plateletlike particles and inhibits proliferation and tumorigenesis.
SO - Blood 2001 Oct 1;98(7):2210-9
AD - Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ontario, Canada.
Rapid proliferation of atypical megakaryoblasts is a characteristic of megakaryoblastic leukemia. Cells from patients with this disorder and cell lines established from this type of leukemia showed the presence of gelsolin but the absence of scinderin expression, 2 filamentous actin-severing proteins present in normal megakaryocytes and platelets. Vector-mediated expression of scinderin in the megakaryoblastic cell line MEG-01 induced a decrease in both F-actin and gelsolin. This was accompanied by increased Rac2 expression and by activation of the PAK/MEKK.SEK/JNK/c-jun, c-fos transduction pathway. The Raf/MEK/ERK pathway was also activated in these cells. Transduction pathway activation was followed by cell differentiation, polyploidization, maturation, and apoptosis with release of platelet-like particles. Particles expressed surface CD41a antigen (glycoprotein IIb/IIIa or fibrinogen receptor), had dense bodies, high-affinity serotonin transport, and circular array of microtubules. Treatment of particles with thrombin induced serotonin release and aggregation that was blocked by CD41a antibodies. PAC-1 antibodies also blocked aggregation. Exposure of cells to PD98059, a blocker of MEK, inhibited antigen CD41a expression, increases in cell volume, and number of protoplasmic extensions. Cell proliferation and cell ability to form tumors in nude mice were also inhibited by the expression of scinderin. MEG-01 cells expressing scinderin had the same fate in vivo as in culture. Thus, when injected into nude mice, they entered apoptosis and released platelet-like particles. The lack of scinderin expression in megakaryoblastic leukemia cells seems to be responsible for their inability to enter into differentiation and maturation pathways characteristic of their normal counterparts.
UI - 11568911
AU - Alessandri AJ; Knezevich SR; Mathers JA; Schultz KR; Sorensen PH
TI - Absence of t(12;15) associated ETV6-NTRK3 fusion transcripts in pediatric acute leukemias.
SO - Med Pediatr Oncol 2001 Oct;37(4):415-6
AD - Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, University of British Columbia and Children's and Women's Hospital, Vancouver, BC, Canada V5Z 4H4.
UI - 11574770
AU - Boll IT
TI - Documentation of normal and leukemic myelopoietic progenitor cells with high-resolution phase-contrast time-lapse cinematography.
SO - Onkologie 2001 Aug;24(4):395-402
AD - II. Internal Department, Hospital Neukolln, Germany. email@example.com
The high-resolution phase-contrast, time-lapse cinematography using oil immersion lenses and 16-mm film demonstrates the kinetic cell events as maturation, locomotion, mitosis, and apoptosis of cells cultivated at 37 degrees C for up to 10 days. 0.5 v/v frozen-thawed sera with presumably high cytokine concentrations were added to the plasma or agar clot. Vital progenitor cells from human bone marrow and blood have a large, bright, unstructured nucleus with a large nucleolus and a narrow rim of cytoplasm (nuclear/cytoplasmic volume ratio = 0.7). Their nuclei are 6-14 micrometer in diameter and double their volume within 8 h. Many (70%) move at a mean speed of 2 micrometer/min, and many (30%) multiply with alpha-2alpha mitoses, generating progenitor cell families. Various disturbances during the course of mitosis lead to the formation of polyploid cells, thereby yielding the megakaryocytic cell line. Some of the progenitor cells undergo asymmetric alpha-alphan mitoses: One of the two initially identical daughter cells remains a progenitor cell in the morphological sense, whereas the other daughter cell - depending on the size of its mother cell - matures in the same culture medium to form a granulocytopoietic, monocytopoietic or erythrocytopoietic cell line. - In acute myeloid leukemias (AML), the blasts and their nuclei are slightly larger than the corresponding progenitor cells and move faster (5 micrometer/min). Symmetric alpha-2alpha mitoses permit unlimited multiplication of the leukemic blasts if contact with cytotoxic lymphocytes does not render them apoptotic. This results in more stromal cells than normal. Granulocytopenia, monocytopenia, and anemia occur due to the genetic impairment of signaling control for asymmetric alpha-alphan mitoses, and thrombocytopenia occurs due to the reduction in polyploidization. Copyright 2001 S. Karger GmbH, Freiburg
UI - 11579461
AU - Eguchi M; Eguchi-Ishimae M; Seto M; Morishita K; Suzuki K; Ueda R; Ueda
TI - K; Kamada N; Greaves M GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24).
SO - Genes Chromosomes Cancer 2001 Nov;32(3):212-21
AD - Leukaemia Research Fund Centre, Institute of Cancer Research, London, United Kingdom. firstname.lastname@example.org
We report a novel MLL-associated chromosome translocation t(11;14)(q23;q24) in a child who showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase-II inhibitor VP 16. Screening of a cDNA library of the patient's leukemic cells showed a novel fusion transcript between MLL and the Gephyrin (GPHN) gene on 14q24. The resulting MLL-GPHN fusion gene encodes MLL AT hook motifs and a DNA methyltransferase homology domain fused to the C-terminal half of Gephyrin, including a presumed tubulin binding site and a domain homologous to the Escherichia coli molybdenum cofactor biosynthesis protein MoeA. Genomic breakpoint analysis showed potential in vitro topoisomerase-II DNA-binding sites spanning the breakpoints in both MLL and GPHN but no flanking sequences that might mediate homologous recombination. This suggests that MLL-GPHN may have been generated by VP 16/topoisomerase-II-induced DNA double-strand breaks, followed by error-prone DNA repair via non-homologous end joining. Gephyrin was originally identified as a submembraneous scaffold protein that anchors and immobilizes postsynaptic membrane neurotransmitter receptors to underlying cytoskeletal elements. It also is reported to bind to phosphatidylinositol 3,4,5-triphosphate binding proteins involved in actin dynamics and downstream signaling and interacts with ATM-related family member RAFT1. Gephyrin domains in the chimeric protein therefore could contribute novel signal sequences or might modify MLL activity by oligomerization or intracellular redistribution. Copyright 2001 Wiley-Liss, Inc.
UI - 11579469
AU - Alvarez S; MacGrogan D; Calasanz MJ; Nimer SD; Jhanwar SC
TI - Frequent gain of chromosome 19 in megakaryoblastic leukemias detected by comparative genomic hybridization.
SO - Genes Chromosomes Cancer 2001 Nov;32(3):285-93
AD - Laboratory of Molecular Aspects of Hematopoiesis, Sloan-Kettering Institute for Cancer Research, New York, New York 10021, USA.
Acute megakaryocytic leukemia is a rare subtype of AML that is often difficult to diagnose; it is most commonly associated with Down syndrome in children. To identify chromosomal imbalances and rearrangements associated with acute megakaryocytic leukemia, we used G-banding, comparative genomic hybridization (CGH), and whole chromosome painting (WCP) on a variety of primary patients' samples and leukemia cell lines. The most common abnormality was gain of chromosome 19 or arm 19q, which was detected by CGH in four of 12 (33.3%) primary samples and nine of 11 (81.8%) cell lines. In none of the primary samples was this abnormality detected by G-banding analysis. WCP was used to define further the nature of the chromosome 19 gain in the cell lines, which was found to be due to the presence of additional 19q material on marker chromosomes or to cryptic translocations involving 19q. The most common chromosomal loss--detected only in the cell lines--was deletion of chromosomal band 13q14, which was seen in six of 11 (54.5%) cell lines. Other recurrent changes included gains of 1p, 6p, 8q, 11q, 15q, 17q, and 21q and losses of 2, 4q, 5q, 7q, 9p, and 11p. Combining conventional and molecular cytogenetic analyses defined recurrent clonal chromosomal abnormalities, which will aid in the identification of critical genes that are abnormal in acute megakaryocytic leukemia cells. Copyright 2001 Wiley-Liss, Inc.
UI - 11593538
AU - Chen Z; Wang W; Pan J; Chen L; Xue Y
TI - Combination of all-trans retinoic acid with butyric acid and its prodrugs markedly enhancing differentiation of human acute promyelocytic leukemia NB4 cells.
SO - Chin Med J (Engl) 1999 Apr;112(4):352-5
AD - Jiangsu Institute of Hematology, First Affiliated Hospital, Suzhou Medical College, Suzhou 215006, China.
OBJECTIVE: To use NB4, an authentic human acute promyelocytic leukemia cell line, as well as the marrow cells from patients with acute promyelocytic leukemia (APL), containing the PML/RAR alpha fusion gene and fused protein to examine the growth inhibition and cytodifferentiation induced by all-trans retinoic acid (ATRA), butyric acid (BA) and its prodrug tributyrin (TB) either as a single agent or in combinations. METHODS: NB4 and APL cells were cultured in presence of ATRA, BA and TB respectively either as a single agent or in combinations at various concentration ratio. Cell growth was measured and myeloid differentiation was determined by morphology and the percentage of positive nitroblue tetrazolium reduction (NBT) on consecutive days over the whole process of culture. RESULTS: NB4 cells can be induced by ATRA alone and synergistically induced by the combinations of BA or TB with ATRA to differentiate. The synergy was reflected by a remarkable decrease in the effective concentration of ATRA required in the combinations in comparison with it as a sole agent. The combinations also shortened the time for the cells to reach the same level of maturation as that needed for ATRA alone. The potentiation on ATRA-induced differentiation of NB4 cells seemed depending on an appropriate concentration ratio of each inducer in the combinations and the time of action. A preliminary result of in vitro induction of primarily cultured leukemic cells from APL patients by the combined inducers was promising. CONCLUSION: The combinations of ATRA with BA or TB at an appropriate ratio may improve the clinical outcome of differentiation therapy for APL patients.
UI - 11601208
AU - Zhang X; Chen Y; Wang X
TI - [Experimental study of cord blood plasma enhancing the anti-leukemia effect of Ara-C]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 May;20(5):229-31
AD - Department of Hematology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006.
OBJECTIVE: To study the in vitro effect of cord blood plasma(CBP) on the sensitivity of acute myeloid leukemia(AML) cells to cytosine arabinoside (Ara-C). METHODS: Cytotoxicity of Ara-C was detected by MTT assay in twenty-eight patients. RESULTS AND CONCLUSION: The sensitivity of AML cells to Ara-C was heterogeneous, but CBP could significantly enhanced the cytotoxic activity of Ara-C to drug resistant AML cells.
UI - 11601243
AU - Bao Y; Yu R; Zhang D
TI - [In vitro study on cellular and molecular mechanism of tripterine treating leukemic mast cells]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Mar;20(3):146-8
AD - Clinical Immunology Center of PLA, Changzheng Hospital, Second Military Medical University, Shanghai 200003.
OBJECTIVE: To explore the effect of tripterine on leukemic mast cells. METHODS: The human leukemic mast cell line (HMC-1) was used as target cells for the tripterine's effect. RESULTS: 1. Apoptosis of HMC-1 cells could be efficiently induced by tripterine (0.125-1.0 mumol/L), showing the apoptotic changes in morphology, DNA ladder on argarose gel electrophoresis and apoptotic peak before G1 phase of cell cycle on flowcytometry. 2. The magnitude of apoptosis increased with the augmentation of tripterine concentration and duration of exposure; 3. With G1 phase cells decreasing, S phase cells were increased, and then apoptotic cells increased with a diminution of S phase cells. They bored significant negative relation (P < 0.01); 4. Tripterine could upregulate Bax, c-myc expression and downregulate bcl-2 expression at protein level. CONCLUSION: Tripterine can efficiently induce HMC-1 cell apoptosis, occurring mainly in S phase, which is correlated with upregulating Bax, c-myc expression and downregulating bcl-2 expression.
UI - 11601201
AU - Guo X; Xu S; Dong Z
TI - [WT1 gene expression in leukemia patients and its correlation with prognosis and multidrug resistance]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Feb;20(2):69-72
AD - Department of Hematology, Second Hospital, Hebei Medical University, Shijiazhuang 050000.
OBJECTIVE: To evaluate the value of expression of WT1 gene in predicting the prognosis of leukemia patients, and explore the relationship between WT1 gene expression and multidrug resistance and cell apoptosis. METHODS: Expressions of WT1, MRP and mdr1 were measured in 68 leukemia patients by RT-PCR method. Expression of bcl-2 was measured in 32 AML patients by immunofluorescence flow cytometry. RESULTS: Expression of WT1 was revealed in 36 of 68 leukemia patients and none of 23 normal controls. Complete remission rate (59.46%) was lower in WT1 positive patients than that (87.10%, P = 0.011) in WT1 negative patients. The rate of MRP expression was also higher in patients with WT1 expression (58.33%), than in those without WT1 expression (32.26%, P = 0.033). Thirty-two AML patients were divided into high-, intermediate-, and low-risk groups according to the expression of WT1 and bcl-2. CR rates were significantly different among these 3 groups (33.33% for high-, 47.37% for intermediate-, and 100% for low-risk group, P < 0.05). CONCLUSION: The expression of WT1 can predict the treatment outcome and the prognosis for leukemia patients. Expression of WT1 is the most important risk factor, and the coexpression of WT1 and bcl-2 predicts poor prognosis of AML patients.
UI - 11601207
AU - Hua D; Li J; Xia X
TI - [Immunophenotype and P-glycoprotein expression in CD7 positive adult acute myeloid leukemia]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Feb;20(2):88-90
AD - First Affiliated Hospital, Suzhou Medical College, Jiangsu Institute of Hematology, Suzhou 215006.
OBJECTIVE: To study the immunophenotype and P-glycoprotein expression in CD7 positive adult acute myeloid leukemia (CD7+ AML). METHODS: Morphology, P-glycoprotein, cytogenetics and immunophenotype were examined in 30 previously untreated CD7+ AML patients. RESULTS: The CD7 positive rate was 11.4% in 262 AML patients. CD7+ AML patients had a significantly higher incidence of peripheral leukocytosis and blasts and FAB M1 subtype and were associated with CD34 and P-glycoprotein expression. 42.3% of CD7+ AML achieved complete remission with a median remission duration of 4 months, and a median time to CR of 48 days. CONCLUSION: Patients with CD7+ AML are usually CD34 and P-glycoprotein positive. These patients had a lower CR rate and a shorter remission duration.
UI - 11672771
AU - Liu S; Li Q; Pang W; Bo L; Qin S; Liu X; Teng Q; Qian L; Wang J
TI - A new complex variant t(4;15;17) in acute promyelocytic leukemia: fluorescence in situ hybridization confirmation and literature review.
SO - Cancer Genet Cytogenet 2001 Oct 1;130(1):33-7
AD - Laboratory of Genetics, Hematological Institute, Chinese Academy of Medical Sciences, 288 Nanjing Road, 300020, Tianjin, China.
We report a 37-year-old male with acute promyelocytic leukemia (APL) harboring a complex translocation (4;15;17). Karyotypic analysis with R-banding of bone marrow cells revealed 46,XY,t(4;15;17)(q21;q22;q21). Fluorescence in situ hybridization analysis using painting probes for chromosomes 4, 15 and 17 and reverse transcriptase polymerase chain reaction analysis revealed three derivative chromosomes: der(4)t(4;15)(q21;q22), der(15)t(4;15;17)(q21;q22;q21), and del(17)(q21q22). This is the third report of such a translocation and the first confirmed by molecular methods. Considering reported similar cases, it is possible that 4q21 is a nonrandom breakpoint in APL with complex translocations and the gene involved in 4q21 should be investigated.
UI - 11675334
AU - Jurcic JG; Nimer SD; Scheinberg DA; DeBlasio T; Warrell RP Jr; Miller WH
TI - Jr Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia.
SO - Blood 2001 Nov 1;98(9):2651-6
AD - Leukemia, Hematology, and Developmental Chemotherapy Services, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. email@example.com
The t(15;17) translocation in acute promyelocytic leukemia (APL) yields a PML/RAR-alpha fusion messenger RNA species that can be detected by reverse transcription-polymerase chain reaction (RT-PCR) amplification. Breakpoints within intron 3 of PML produce a short PML/RAR-alpha isoform, whereas breakpoints within intron 6 result in a longer form. Using RT-PCR, serial evaluations were performed on the bone marrow of 82 patients with APL (median follow-up, > 63 months) who received retinoic acid (RA) induction followed by postremission treatment with chemotherapy, RA, and biologic agents. Sixty-four patients attained a clinical complete remission and had at least 2 RT-PCR assays performed after completing therapy. Forty of 47 patients (85%) with newly diagnosed APL who were induced using RA had residual disease detectable by RT-PCR before additional therapy. After 3 cycles of consolidation therapy, residual disease was found in only 4 of 40 evaluable patients (10%). Among newly diagnosed patients who had 2 or more negative RT-PCR assays, only 3 of 41 (7%) had a relapse, whereas all 4 patients (100%) who had 2 or more positive results had a relapse. Among 63 newly diagnosed patients, those who expressed the short isoform appeared to have shorter disease-free and overall survival durations than patients who expressed the long isoform. These data indicate that 2 or more negative RT-PCR assays on bone marrow, performed at least 1 month apart after completing therapy, are strongly associated with long-term remissions. Conversely, a confirmed positive test is highly predictive of relapse.
UI - 11675363
AU - Cassinat B; Chevret S; Zassadowski F; Balitrand N; Guillemot I; Menot
TI - ML; Degos L; Fenaux P; Chomienne C; The European APL Group In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome.
SO - Blood 2001 Nov 1;98(9):2862-4
AD - Laboratoire de Biologie Cellulaire Hematopoietique, Nuclear Medicine Department, Saint-Louis Hospital, Paris, France.
Acute promyelocytic leukemia (APL) blasts possess a unique sensitivity to the differentiating effects of all-trans retinoic acid (ATRA). Multicenter trials confirm that the combination of differentiation and cytotoxic therapy prolongs survival in APL patients. However relapses still occur, and exquisite adaptation of therapy to prognostic factors is essential to aim at a possible cure of the disease. A heterogeneity was previously reported in the differentiation rate of patients' APL blasts, and it was postulated that this may reflect the in vivo heterogeneous outcome. In this study, it is demonstrated that patients of the APL93 trial whose leukemic cells achieved optimal differentiation with ATRA in vitro at diagnosis had a significantly improved event-free survival (P =.01) and lower relapse rate (P =.04). This analysis highlights the importance of the differentiation step in APL therapy and justifies ongoing studies aimed at identifying novel RA-differentiation enhancers.
UI - 11675138
AU - Paulsson K; Sall T; Fioretos T; Mitelman F; Johansson B
TI - The incidence of trisomy 8 as a sole chromosomal aberration in myeloid malignancies varies in relation to gender, age, prior iatrogenic genotoxic exposure, and morphology.
SO - Cancer Genet Cytogenet 2001 Oct 15;130(2):160-5
AD - Department of Clinical Genetics, Lund University Hospital, SE-221 85, Lund, Sweden. firstname.lastname@example.org
Although trisomy 8 as a sole change is one of the most common chromosomal abnormalities in myeloid malignancies, it is largely unknown if the incidence of this aberration is influenced by other factors of clinical importance. In the present study, the frequencies of isolated +8 in relation to gender, age, previous treatment with chemo- or radiotherapy, and morphologic subtype were ascertained in published, as well as in our own unpublished, cases of acute myeloid leukemia (AML; n=4,246), myelodysplastic syndromes (MDS; n=1,817), and chronic myeloproliferative disorders (MPD; n=530). The frequencies of +8 were higher in MDS and MPD than in AML (7.5% vs. 5.6%; P<0.01) and varied among the morphologic subtypes of AML and MDS (P<0.001 and P<0.05, respectively). Trisomy 8 was more common in women than in men with MPD (11% vs. 5.1%; P<0.05). Furthermore, the frequencies of +8 were higher in de novo AML and MDS than in treatment-related cases (6.0% vs. 2.8%; P<0.01 and 8.6% vs. 1.5%; P<0.001, respectively). The incidence also varied significantly with age in AML (P<0.001), being more common in elderly patients. Although the causes for this frequency heterogeneity remain to be elucidated, possible explanations may include different environmental exposures affecting the origin of +8 in AML, MDS, and MPD and the presence of different underlying cryptic primary aberrations.
UI - 11684280
AU - Stirewalt DL; Willman CL; Radich JP
TI - Quantitative, real-time polymerase chain reactions for FLT3 internal tandem duplications are highly sensitive and specific.
SO - Leuk Res 2001 Dec;25(12):1085-8
AD - Program in Genetics and Genomics, Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Avenue North, Seattle, WA 98109, USA. email@example.com
Internal tandem duplications (ITDs) of the FLT3 gene occur in approximately 20-30% of acute myeloid leukemia (AML) patients. We investigated if FLT3 ITDs could be used as minimal residual disease (MRD) markers for AML patients. Patient-specific polymerase chain reaction (PCR) assays for FLT3 ITDs were developed for four AML samples that contained FLT3 ITDs of varying size and location. The real-time, quantitative PCR assays for FLT3 ITDs were highly sensitive and specific, detecting between 0.01 and 0.001% of FLT3 ITD positive DNA in a background of 1 microg of normal bone marrow DNA. Our findings suggest that FLT3 ITDs can be used as molecular markers for MRD in patients with AML.
UI - 11684286
AU - Balaian L; Ball ED
TI - Direct effect of bispecific anti-CD33 x anti-CD64 antibody on proliferation and signaling in myeloid cells.
SO - Leuk Res 2001 Dec;25(12):1115-25
AD - Department of Medicine and Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA 92093-0960, USA.
Bispecific anti-CD33 x anti-CD64 antibody (BsAb) directly inhibited proliferation and colony formation of human acute myeloid leukemia cell lines, without affecting the function of normal monocytes. Addition of BsAb to normal monocytes induced tyrosine phosphorylation of Cbl and Vav, association of these molecules with CD33, and downstream signaling. In leukemia cells that were insensitive to BsAb treatment, Vav and Cbl were constitutively phosphorylated and, therefore, constitutively associated with CD33. Direct growth inhibition is an additional mechanism by which BsAb may be useful in the therapy of AML.
UI - 11704844
AU - Cassinat B; Chomienne C
TI - Biological features of primary APL blasts: their relevance to the understanding of granulopoiesis, leukemogenesis and patient management.
SO - Oncogene 2001 Oct 29;20(49):7154-60
AD - Hopital Saint-Louis, Paris, Institute of Hematology, INSERM E 00-03 France.
In recent years, discovery of the in vitro and in vivo differentiation of APL blasts by all-trans retinoic acid (ATRA) has modified the therapeutic approach of APL and lead to important advances in understanding the biology of APL. Since it became apparent that differentiation therapy of APL with ATRA was indeed a true model of targetted therapy, evidencing the molecular targets of retinoic acid efficacy became crucial. These molecular targets are closely related to the biological features of APL cells, some of which are well-known and have contributed to the morphological and cytogenetic definition of the leukemia, others have just been defined or re-discovered in the light of a better understanding of molecular controls of cell growth and differentiation. The aims of characterizing the biological features of APL cells should allow a better management of APL therapy and the identification of potential markers for differentiation therapies in other leukemias or solid tumors.
UI - 11704847
AU - Zelent A; Guidez F; Melnick A; Waxman S; Licht JD
TI - Translocations of the RARalpha gene in acute promyelocytic leukemia.
SO - Oncogene 2001 Oct 29;20(49):7186-203
AD - Leukemia Research Fund Centre at the Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK. firstname.lastname@example.org
Acute promyelocytic leukemia (APL) has been recognized as a distinct clinical entity for over 40 years. Although relatively rare among hematopoietic malignancies (approximately 10% of AML cases), this disease has attracted a particularly good share of attention by becoming the first human cancer in which all-trans-retinoic acid (ATRA), a physiologically active derivative of vitamin A, was able to induce complete remission (CR). ATRA induced remission is not associated with rapid cell death, as in the case of conventional chemotherapy, but with a restoration of the 'normal' granulocytic differentiation pathway. With this remarkable medical success story APL has overnight become a paradigm for the differentiation therapy of cancer. A few years later, excitement with APL was further enhanced by the discovery that a cytogenetic marker for this disease, the t(15:17) reciprocal chromosomal translocation, involves a fusion between the retinoic acid receptor alpha (RARalpha) gene and a previously unknown locus named promyelocytic leukemia (PML). Consequence of this gene rearrangement is expression of the PML-RARalpha chimeric oncoprotein, which is responsible for the cellular transformation as well as ATRA response that is observed in APL. Since this initial discovery, a number of different translocation partner genes of RARalpha have been reported in rarer cases of APL, strongly suggesting that disruption of RARalpha underlies its pathogenesis. This article reviews various rearrangements of the RARalpha gene that have so far been described in literature, functions of the proteins encoded by the different RARal
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