National Cancer Institute®
Last Modified: August 1, 2002
UI - 12091906
AU - Linggi B; Muller-Tidow C; van de Locht L; Hu M; Nip J; Serve H; Berdel
TI - WE; van der Reijden B; Quelle DE; Rowley JD; Cleveland J; Jansen JH; Pandolfi PP; Hiebert SW The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia.
SO - Nat Med 2002 Jul;8(7):743-50
AD - Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
The t(8;21) is one of the most frequent chromosomal translocations associated with acute leukemia. This translocation creates a fusion protein consisting of the acute myeloid leukemia-1 transcription factor and the eight-twenty-one corepressor (AML1 ETO), which represses transcription through AML1 (RUNX1) DNA binding sites and immortalizes hematopoietic progenitor cells. We have identified the p14(ARF) tumor suppressor, a mediator of the p53 oncogene checkpoint, as a direct transcriptional target of AML1 ETO. AML1 ETO repressed the p14(ARF) promoter and reduced endogenous levels of p14(ARF) expression in multiple cell types. In contrast, AML1 stimulated p14(ARF) expression and induced phenotypes consistent with cellular senescence. Chromatin immunoprecipitation assays demonstrated that AML1 ETO was specifically bound to the p14(ARF) promoter. In acute myeloid leukemia samples containing the t(8;21), levels of p14(ARF) mRNA were markedly lower when compared with other acute myeloid leukemias lacking this translocation. Repression of p14(ARF) may explain why p53 is not mutated in t(8;21)-containing leukemias and suggests that p14(ARF) is an important tumor suppressor in a large number of human leukemias.
UI - 12142392
AU - Applegate TL; Iland HJ; Mokany E; Todd AV
TI - Diagnosis and molecular monitoring of acute promyelocytic leukemia using DzyNA reverse transcription-PCR to quantify PML/RARalpha fusion transcripts.
SO - Clin Chem 2002 Aug;48(8):1338-43
AD - Johnson & Johnson Research Pty Limited, Australian Technology Park, Eveleigh NSW 1430, Australia. firstname.lastname@example.org
BACKGROUND: PML/RARalpha fusion transcripts provide a readily accessible marker for diagnosis of acute promyelocytic leukemia (APL) and for monitoring response to therapy. Survival rates are improved by therapies guided by such monitoring. We assessed the potential of DzyNA reverse transcription-PCR (RT-PCR) for measurement of PML/RARalpha fusion transcripts. METHODS: Parallel single-tube DzyNA RT-PCR protocols were developed to allow real-time fluorescent quantification of PML/RARalpha fusion transcripts and a low abundance control transcript, normal BCR. Calibration curves, generated using cell line RNA, allowed estimation of these transcripts in RNA from patients with APL at various stages of the disease. RESULTS: DzyNA RT-PCR calibration curves were linear for both transcripts over a broad range and demonstrated interassay variations of 12% (mean, 658 ng) and 10% (mean, 263 ng), respectively. The protocols detected low concentrations of transcripts and resolved twofold dilutions. PML/RARalpha mRNA was quantified in 10 patients at diagnosis and in 1 patient over a 7-year period. Monitoring of transcript concentrations effectively reflected the disease course in one patient and demonstrated that an increase in PML/RARalpha transcripts can be detected 4-6 months before hematologic relapse, with no false-positive results. CONCLUSION: DzyNA RT-PCR has potential for use in clinical practice as a tool for diagnosis of APL and forsubsequent monitoring of minimal residual disease and detection of molecular relapse.
UI - 12138666
AU - Shivakumar S; Poonkhuzhali B; Gunasekaran S; Srivastava A; Chandy M
TI - Cytogenetic, fluorescent in situ hybridization & reverse transcriptase-polymerase chain reaction analysis in acute promyelocytic leukaemia patients.
SO - Indian J Med Res 2002 Feb;115():59-67
AD - Departments of Haematology, Christian Medical College & Hospital, Vellore, India.
BACKGROUND & OBJECTIVES: The presence of t(15;17) or PML-RAR alpha fusion transcript is the diagnostic hallmark of patients with acute promyelocytic leukaemia (APL). Cytogenetic (CG), fluorescent in situ hybridization (FISH) and reverse transcriptase-polymerase chain reaction (RT-PCR) are mainly the techniques used for detecting this abnormality. The objective of this study was to compare and assess the role of CG, FISH and RT-PCR in the diagnosis of APL. METHODS: CG, FISH and RT-PCR analysis were performed in 29 patients with APL (28 M3, 1 M3v; 27 studied at diagnosis and 2 at relapse). RESULTS: Karotypes obtained in 25 patients revealed t(15;17) in 21 normal karyotype in 3 and trisomy 8 in 1 patient. In 26 patients FISH was positive for PML-RAR alpha fusion in both interphase (IP) and metaphase, two were negative and one patient had no cells for FISH analysis. IP FISH confirmed the fusion of PML-RAR alpha in all patients with t(15;17) detected by CG. RT-PCR was positive in the 22 patients analyzed (7 patients did not have RT-PCR). PCR was positive in the 3 patients with cytogenetically normal karyotypes and in one patient when karyotyping was a failure. CG detected 21 (72.4%) patients with t(15;17) of which additional chromosomal abnormalities were detected in 20 per cent of patients with successful karyotype. INTERPRETATION & CONCLUSION: FISH and RT-PCR were useful in detecting PML-RAR alpha fusion in cytogenetically normal patients and those in when karyotyping was a failure and can be used in routine analysis for rapid confirmation of t(15;17) in patients with acute myeloid leukaemia.
UI - 12008084
AU - Kawamura C; Kizaki M; Fukuchi Y; Ikeda Y
TI - A metal chelator, diphenylthiocarbazone, induces apoptosis in acute promyelocytic leukemia (APL) cells mediated by a caspase-dependent pathway without a modulation of retinoic acid signaling pathways.
SO - Leuk Res 2002 Jul;26(7):661-8
AD - Division of Hematology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
A metal chelator, diphenylthiocarbazone (dithizone), has been reported to induce differentiation and apoptosis of the human myeloid leukemia cell line HL-60, however, very little is known about the mechanism of dithizone-induced apoptosis. Here, we report for the first time that dithizone can induce inhibition of cellular growth of retinoic acid (RA)-sensitive NB4 and RA-resistant UF-1 APL cells via induction of apoptosis but not differentiation. Treatment of NB4 cells with dithizone markedly-induced apoptosis, which was associated with the loss of mitochondrial transmembrane potentials (Delta Psi(m)) and activation of caspase-3 and -9. Further investigation of the RA-resistant UF-1 APL cells showed that dithizone-induced apoptosis to a lesser extent. However, neither dithizone alone nor in combination with all-trans RA induced the expression of myeloid differentiation antigen CD11b. Concomitantly, the degradation of PML/RARalpha fusion protein was not observed after treatment with dithizone alone, and the degradation was not enhanced by the combination of dithizone and all-trans RA. We conclude that dithizone, a metal chelator, induced apoptosis without differentiation in APL cells in association with Delta Psi(m) collapse and caspase-3 and -9 activation.
UI - 11798779
AU - Guo W; Wang H; Zhao W
TI - [Effects of all-trans retinoic acid and arsenic trioxide on tissue factor expression of acute promyelocytic leukemia cells]
SO - Zhonghua Yi Xue Za Zhi 2000 May;80(5):327-31
AD - Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai 200025, China.
OBJECTIVE: To investigate the effects of all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) on both tissue factor (TF) expression and procoagulant activity (PCA) of acute promyelocytic leukemia (APL) cells in vivo and in vitro. METHODS: The PCA of APL blasts freshly isolated from the APL patients treated with ATRA or As(2)O(3) was detected using a one-stage clotting assay; the TF antigen was detected by ELISA and TF mRNA by RT-PCR. The maturation sensitivity (NB4) or resistant subclones (NB4-R1) of the promyelocytic NB4 cell line as well as U937 cells transfected with pMSCV-PML-RARa treated with or without ATRA or As(2)O(3) were also examined. RESULTS: Both ATRA and As(2)O(3) time-dependently down-regulated the TF antigen, its mRNA transcription and membrane PCA of APL cells in vivo and in vitro. The TF antigen level in PML-RARa(+) U937 cells was significantly higher than that in U937 cells transfected with retrovirus vector (890 pg/8 x 10(5) +/- 80 pg/8 x 10(5) cell and 728 pg/8 x 10(5) +/- 86 pg/8 x 10(5) cell, respectively). Both ATRA and As(2)O(3) down-regulated the TF antigen of the U937 cells transfected with or without PML-RARa. CONCLUSION: Tissue factor expression and PCA of APL cells can be down-regulated by ATRA and As(2)O(3). By down-regulating the TF expression, As(2)O(3) might also be used to improve the DIC-related hemorrhage of APL. It is also suggested that elevated TF antigen in the PML-RARa(+) U937 cells may be related with the fusion protein PML-RARa, while the down-regulation effect of ATRA and As(2)O(3) on the TF expression of U937 cells might not be involved in the fusion protein.
UI - 11243400
AU - Sarriera JE; Albitar M; Estrov Z; Gidel C; Aboul-Nasr R; Manshouri T;
TI - Kornblau S; Chang KS; Kantarjian H; Estey E Comparison of outcome in acute myelogenous leukemia patients with translocation (8;21) found by standard cytogenetic analysis and patients with AML1/ETO fusion transcript found only by PCR testing.
SO - Leukemia 2001 Jan;15(1):57-61
AD - Department of Hematology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Patients with normal-karyotype acute myelogenous leukemia (NKAML) may have undetected genetic abnormalities that could affect prognosis. Screening for known AML-specific genetic abnormalities using the reverse transcription polymerase chain reaction (RT-PCR) may help in arriving at a more definitive prognosis. To test this hypothesis, 104 patients without translocation (8;21) and inversion(16), as shown by standard cytogenetic (SC) analysis, were screened for these two genetic abnormalities using RT-PCR. Western blot analysis for the AML1/ETO fusion protein and fluorescent in situ hybridization (FISH) analysis for t(8;21) were performed in patients for whom we had samples. The characteristics and outcome after high-dose cytarabine containing treatments in five patients with t(8;21) shown by RT-PCR alone were then compared to 21 patients with t(8;21) detected using SC analysis. Eight of the 104 patients had masked t(8;21) and none had masked inv(16), as shown by RT-PCR. Five of 54 patients with NKAML had a detectable AML1/ETO fusion RNA transcript. Western blot analysis showed the AML1/ETO fusion protein in four of the seven patients for whom we had samples among the eight with masked t(8;21) shown by RT-PCR. All patients with t(8;21) shown by RT-PCR had negative FISH results. Ninety percent (n=19) of the patients with t(8;21) shown by SC analysis and 40% (n= 2) of the patients with t(8;21) shown by RT-PCR alone achieved a complete remission (P value 0.03). These data suggest that the outcome of NKAML patients with t(8;21) shown by RT-PCR is not equivalent to patients with t(8;21) by SC studies.
UI - 11368449
AU - van den Heuvel-Eibrink MM; Wiemer EA; Kuijpers M; Pieters R; Sonneveld P
TI - Absence of mutations in the deoxycytidine kinase (dCK) gene in patients with relapsed and/or refractory acute myeloid leukemia (AML).
SO - Leukemia 2001 May;15(5):855-6
UI - 11899117
AU - Ekstrom K; Wuu J; Hsieh CC; Glimelius B; Lambe M
TI - Childbearing and the risk of leukemia in Sweden.
SO - Cancer Causes Control 2002 Feb;13(1):47-53
AD - Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden. email@example.com
OBJECTIVE: The possible influence of childbearing on the development of leukemias in females has received little attention, in spite of consistent findings of lower incidence rates in females than in males. A nested case-control study was undertaken to explore if parity and age at first birth affect the risk of developing these malignancies. METHODS: In a nationwide cohort defined by a population-based Fertility Register, we identified 356 women with chronic myeloid leukemia (CML), 819 with acute nonlymphocytic leukemia (ANLL), and 179 with acute lymphocytic leukemia (ALL). For each case, five age-matched controls were selected. Odds ratios were estimated by conditional logistic regression analyses. RESULTS: There was some evidence of weak negative associations between parity and age at first birth for CML. Compared to nulliparous women there was a tendency of a temporal risk reduction of CML for the first 10 years following a delivery. The risk of ANLL was slightly lower in parous compared to nulliparous women. Neither parity nor age at first birth was related to the risk of ALL. CONCLUSIONS: We conclude that if pregnancy-related hormonal or immunological factors have an effect on the development of leukemia, it is minor and confined to the myeloid types, chiefly CML. Our study gives some support for treating the leukemias as separate entities based on both cell lineage and form in future etiologic studies.
UI - 12091356
AU - Dastugue N; Lafage-Pochitaloff M; Pages MP; Radford I; Bastard C;
TI - Talmant P; Mozziconacci MJ; Leonard C; Bilhou-Nabera C; Cabrol C; Capodano AM; Cornillet-Lefebvre P; Lessard M; Mugneret F; Perot C; Taviaux S; Fenneteaux O; Duchayne E; Berger R; Groupe Francais d'Hematologie Cellulaire Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique (GFCH).
SO - Blood 2002 Jul 15;100(2):618-26
AD - Centre Hospitalier Universitaire (CHU), Toulouse, France. firstname.lastname@example.org
To draw the cytogenetic profile of childhood and adult acute megakaryoblastic leukemia (M7), the Groupe Francais de Cytogenetique Hematologique collected 53 cases of M7 (30 children and 23 adults). Compared to other acute myeloid leukemias, M7 is characterized by a higher incidence of abnormalities, a higher complexity of karyotypes, and a different distribution of abnormalities among children and adults. Nine cytogenetic groups were identified: normal karyotypes (group 1), patients with Down syndrome (group 2), numerical abnormalities only (group 3), t(1;22)(p13;q13) or OTT-MAL transcript (group 4), t(9;22)(q34;q11) (group 5), 3q21q26 (group 6), -5/del(5q) or -7/del(7q) or both (group 7), i(12)(p10) (group 8), and other structural changes (group 9). Groups 1, 2, 3, and 4 were exclusively composed of children (except one adult in group 3), whereas groups 5, 6, 7, and 8 were mainly made up of adults. The main clinical and hematologic features of these groups were described. No new recurrent abnormality was identified, but mapping of all breakpoints allowed us to specify several possible hot spots of rearrangement: 17q22-23, 11q14-21, 21q21-22, and 16q21-22-23. Although 90.5% of cases had no documented antecedent hematologic disorder or exposure to chemotherapy or radiotherapy, the morphologic and the cytogenetic findings indicated that M7 might be a secondary leukemia more often than suggested by preceding history, particularly among adults. The concurrent analyses of morphologic and cytogenetic data also led us to assume that the initial precursor involved might be more immature in adult than in childhood M7.
UI - 12111118
AU - Galea-Lauri J; Darling D; Mufti G; Harrison P; Farzaneh F
TI - Eliciting cytotoxic T lymphocytes against acute myeloid leukemia-derived antigens: evaluation of dendritic cell-leukemia cell hybrids and other antigen-loading strategies for dendritic cell-based vaccination.
SO - Cancer Immunol Immunother 2002 Aug;51(6):299-310
AD - Department of Molecular Medicine, The Rayne Institute, GKT School of Medicine and Dentistry, 123 Coldharbour Lane, London, SE5 9NU, UK.
Dendritic cells (DC) have been successfully used in clinical pilot studies to induce tumor-specific immunity as well as clinical response in selected patients. However, DC-based immunotherapy remains a challenge and several parameters need to be examined in order to optimize the induction of anti-tumor immune responses. This study focuses on DC vaccination for leukemia and evaluates the in vitro efficacy of three different strategies for generating antigen-loaded DC-based vaccines for the induction of major histocompatibility complex (MHC) class I-restricted anti-leukemia cytotoxic T lymphocyte (CTL) responses. These included direct fusion of DC with leukemia cells to generate DC-leukemia cell hybrids, and DC pulsed with either apoptotic leukemia cell fragments or whole tumor cell lysates. Using either the U937 cell line or primary human acute myeloid leukemia blasts (AML), DC-leukemia cell hybrids were found to be the most potent in vitro inducers of CTL activity. DC pulsed with apoptotic tumor cell fragments were less efficient, but induced a more potent CTL response compared to tumor lysate-pulsed DC. The CTL responses were both MHC class I-restricted and antigen-specific, as shown by the inability of the CTL to lyse other control targets. The data presented here suggest that the method of antigen loading onto DC may be critical in the design of tumor vaccines.
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