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NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of AML - June 2002
National Cancer Institute®
Last Modified: June 1, 2002
- Functional G-CSF pathways in t(8;21) leukemic cells allow for differentiation induction and degradation of AML1-ETO.
- Selective bowel decontamination for the prevention of infection in acute myelogenous leukemia: a prospective randomized trial.
- The role of T cell costimulation by CD80 in the initiation and maintenance of the immune response to human leukemia.
- Radiation-induced leukemia.
- Remodeling of vimentin cytoskeleton correlates with enhanced motility of promyelocytic leukemia cells during differentiation induced by retinoic
- Chromosome 16 inversion-associated translocations in acute myeloid leukemia elucidated using a dual-color CBFB DNA probe.
- Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling
- Hypermethylation of the imprinted NNAT locus occurs frequently in pediatric acute leukemia.
- Comments on the paper: Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors.
- Comments on the paper: Microsatellite instability in acute myelocytic leukaemia developed from A-bomb survivors--and related cytogenic data.
- A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia cells through a defective pathway in telomerase regulation.
- Synergistic induction of apoptosis by simultaneous disruption of the Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia.
- Systemic antifungal prophylaxis reduces invasive fungal in acute myelogenous leukemia: a retrospective review of 833 episodes of
- Rare recurring balanced chromosome abnormalities in therapy-related myelodysplastic syndromes and acute leukemia: report from an
- Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of
- Feasibility and clinical significance of real-time quantitative RT-PCR assay of PML-RARalpha fusion transcript in patients with acute
Table of Contents
1
UI - 11920209
AU - Da Silva N; Meyer-Monard S; Menot ML; Parrado A; Lebel A; Balitrand N;
TI -
Fenaux P; Miclea JM; Rousselot P; Degos L; Dombret H; Chomienne C
Functional G-CSF pathways in t(8;21) leukemic cells allow for
differentiation induction and degradation of AML1-ETO.
SO - Hematol J 2000;1(5):316-28
AD - Laboratoire de Biologie Cellulaire Hematopoietique (LBCH), INSERM E
00-03, et EA 316 Universite Paris 7, Hopital Saint-Louis, 1 Avenue
Claude Vellefaux, 75754 Paris Cedex 10, France. lbch@chu.stlouis.fr
INTRODUCTION: Efficacy of differentiating agents requires that their
specific cellular targets are still expressed and functional in the
leukemic cells. One hypothesis to target sensitive cells is to select
leukemic clones which harbor disrupted transcription factors. CBFalpha
and CBFbeta are core-binding proteins which have been identified as
transcription regulators of hematopoietic genes and shown to be altered
in numerous leukemias. In M2 AML, the t(8;21) translocation, CBFalpha
(AML1) is altered and produced as the AML1-ETO fusion protein. The
fusion protein blocks transcription and differentiation mediated by
G-CSF. Interestingly, AML1-ETO leukemic cell lines are sensitive to
numerous cytokines in vitro and can be induced to differentiate in the
presence of G-CSF and PMA. MATERIALS AND METHODS: As in the APL
differentiation model, primary culture provides a useful tool for
therapeutic screening of differentiation inducers, we analysed the in
vitro sensitivity of 10 fresh M2 AML t(8;21) leukemic samples to G-CSF
and the functionality of G-CSF intracellular pathways. In vitro data
were compared with in vivo data from four patients treated with rhG-CSF
at the dosage of 5 microg/kg/day i.v. for two to three weeks before the
initiation of AML induction chemotherapy and immunophenotypic analysis
performed weekly to monitor in vivo differentiation. RESULTS: In vitro,
an increase in CD34+ cells expressing differentiation antigens (CD11b,
CD13 or CD15) was noted along with a decrease of immature
CD34+/differentiation antigen negative cells. After two weeks of a daily
rhG-CSF administration in vivo, a significant, albeit transient,
decrease of blast count was achieved, concomitant with an increase in
differentiated leukemic cells suggesting that in vivo differentiation
occurs. Fresh t(8;21) leukemic cells possess functional G-CSF signaling
pathways as normal activity and kinetics of STAT1 and STAT3 binding was
observed. Furthermore, differentiation induction leads to a subsequent
degradation of the AML1-ETO oncoprotein. CONCLUSION: The data presented
here supports the claim that G-CSF can induce in vitro and in vivo
differentiation of M2 AML t(8;21) cells.
2
UI - 12014211
AU - Lee DG; Choi SM; Choi JH; Yoo JH; Park YH; Kim YJ; Lee S; Min CK; Kim
TI -
HJ; Kim DW; Lee JW; Min WS; Shin WS; Kim CC
Selective bowel decontamination for the prevention of infection in acute
myelogenous leukemia: a prospective randomized trial.
SO - Korean J Intern Med 2002 Mar;17(1):38-44
AD - Department of Internal Medicine, Catholic University College of
Medicine, Seoul, Korea.
BACKGROUND: Infection is still a frequent cause of morbidity and
mortality in acute myelogenous leukemia (AML) patients receiving
chemotherapy. Recently the main cause of infection has changed from
gram-negative to gram-positive bacteria and the resistance to
antibiotics has increased. This study aimed to access the effectiveness
of antimicrobial prophylaxis (AP) with orally absorbable antibiotics.
METHODS: Ninety-five AML patients receiving chemotherapy at Catholic
1999 were randomly divided into the AP group (250 mg ciprofloxacin twice
a day, 150 mg roxithromycin twice a day, 50 mg fluconazole once a day)
and the control group for a prospective analysis. RESULTS: The incidence
of fever was 82.6% in the AP group and 91.6% in the control group (p =
0.15). Though classification and sites of infections showed no
difference between the two groups, the catheter associated infection
occurred more frequently in the AP group in significance. The time
interval between initiation of chemotherapy and onset of fever, white
blood cell (WBC) count at the onset of fever, duration of leukopenia
(WBC < 1,000/mm3), duration of systemic antibiotic therapy, mortality
due to infection and hospitalization period from the data starting
chemotherapy showed no differences between the two groups. Infections
due to gram negative bacteria decreased to 33.3% in the AP group (vs.
92% in the control group), but infections due to gram positive bacteria
increased to 66.7% (vs. 8% in the control group). Gram negative bacteria
showed 100% resistance to ciprofloxacin in the AP group and
gram-positive bacteria showed 90-100% resistance to erythromycin,
regardless of the presence of AP. CONCLUSION: The AP could not reduce
the occurrence of infection or infection associated death in AML
patients receiving chemotherapy. On considering increased gram-positive
infection and resistance to fluoroquinolone and macrolide, routine
prescription of AP should be reconsidered. Further studies that assess
the effectiveness of AP in other malignancies, aplastic anemia and bone
marrow transplantation are required.
3
UI - 10609780
AU - Matsumoto K; Anasetti C
TI -
The role of T cell costimulation by CD80 in the initiation and
maintenance of the immune response to human leukemia.
SO - Leuk Lymphoma 1999 Nov;35(5-6):427-35
AD - Clinical Research Division, Fred Hutchinson Cancer Research Center,
Seattle, WA 98109, USA.
Most human myeloid leukemias express both class I and class II HLA and
it has been postulated that leukemia-associated peptides are presented
by those molecules. It is possible, however, that leukemia cells escape
the immune surveillance by lacking expression of "costimulatory"
molecules required for activating the immune response. Human
erythroleukemia line (HEL) has been the subject of previous detailed
studies demonstrating surface expression of bona fide HLA molecules but
inability to stimulate allogeneic response of proliferative or cytolytic
T cells. We found that an HLA-DR+ subclone (HEL-DR+) expresses LFA-1,
LFA-3, ICAM-1, ICAM-3, but neither CD80 nor CD86 on the surface.
Transfection of CD80 cDNA into HEL-DR+ cells induced the allogeneic
response of purified T cells from both cord blood and peripheral blood
of adult donors, demonstrating that CD80 expression could lead to
accessory cell-independent activation of naive T cells. Priming
allogeneic peripheral blood T cells by HEL-DR+/CD80+ also lead to
generation of cytotoxic T lymphocytes that lysed both HEL-DR+/CD80+ and
wild type HEL-DR+ equally well, confirming CD80 expression is required
only in the CTL induction phase but not in the CTL effector phase. We
established and maintained alloproliferative T cell clones from adult
blood by stimulation with the HEL-DR+/CD80+ line. The clones could
respond not only to HEL-DR+/CD80+ line but also to the HEL-DR+ line;
however, the proliferative response to HEL-DR+/CD80+ was amplified and
sustained compared to the short-lived response to wild type HEL-DR+
cells. Therefore, expression of CD80 by HEL-DR+ cells was determinant
both to initiate and sustain the T cell response. These experiments
support the hypothesis that lack of expression of "costimulatory"
molecules for T cells contributes to leukemia escape from immune
surveillance, and provide preliminary data for the use of CD80
transfection in the immunotherapy of human leukemia.
4
UI - 11263441
AU - Finch SC
TI -
Radiation-induced leukemia.
SO - Blood 2001 Mar 15;97(6):1897-8
5
UI - 11911279
AU - Bruel A; Paschke S; Jainta S; Zhang Y; Vassy J; Rigaut JP; Beil M
TI -
Remodeling of vimentin cytoskeleton correlates with enhanced motility of
promyelocytic leukemia cells during differentiation induced by retinoic
acid.
SO - Anticancer Res 2001 Nov-Dec;21(6A):3973-80
AD - Institute of Hematology, Hospital St. Louis, Paris, France.
abruel@jupiter.chu-stlouis.fr
The intermediate filament (IFs) cytoskeleton is one of the major
determinants for the mechanical properties of cytoplasm. Vimentin is the
major IFs protein in peripheral blood neutrophils. We investigated its
expression and function during neutrophil differentiation using the
promyelocytic leukemia cell line NB4. The differentiation of NB4 cells
along the neutrophil lineage and the monocytic pathway was induced by
all-trans retinoic acid (ATRA) and phorbol esters (PMA), respectively.
We demonstrated a down-regulation of vimentin after ATRA treatment of
NB4 cells by immunoblotting and immunofluorescence. The architecture of
the vimentin cytoskeleton in differentiated NB4 cells resembled that
observed in mature neutrophils. In contrast, we showed a slight increase
of vimentin content in phorbol ester (PMA)-treated NB4 cells. The
structural features of the vimentin cytoskeleton obtained by image
analysis showed significant differences in network density and
directionality between ATRA-treated NB4 cells and controls. The
functional consequence of the cytoskeletal remodeling for the mechanical
properties of NB4 cells was assessed in migration assays. After ATRA
treatment, we found a 4-fold increased migration of NB4 cells across
transwell membranes with a 8 microm pore size without any cell size
modification. No significant differences between PMA-treated NB4 cells
and control cells could be observed using similar tests. These results
indicate that both vimentin expression and network architecture are
tightly controlled during neutrophil differentiation to regulate the
mechanical properties of these cells.
6
UI - 12034528
AU - Aventin A; Espadaler M; Casas S; Duarte J; Nomdedeu J; Sierra J
TI -
Chromosome 16 inversion-associated translocations in acute myeloid
leukemia elucidated using a dual-color CBFB DNA probe.
SO - Cancer Genet Cytogenet 2002 Apr 15;134(2):142-4
AD - Department of Hematology, University Hospital Sant Pau, Barcelona,
Spain. aaventin@hsp.santpau.es
We describe two cases of acute myelomonocytic leukemia with eosinophilia
(AML-M4Eo) that were diagnosed with an inv(16)(p13q22) based on
conventional cytogenetics (CC) and fluorescence in situ hybridization
(FISH) technique using a chromosome 16p arm specific paint probe.
Additional FISH analysis with a dual-color CBFB DNA probe showed that
the 3' portion of the CBFB gene was translocated to chromosome 10p13 in
the first patient and 1p36 in the other. These two cases indicate that
some inv(16)(p13q22) identified by CC and FISH with chromosome
arm-specific painting probe may represent cases of inversion-associated
translocation. We suggest that all cases with inv(16)(p13q22) should be
investigated by FISH with appropriate probes for a possible
translocation of 16q22-->qter to another chromosome.
7
UI - 11929748
AU - Dong S; Tweardy DJ
TI -
Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia
fusion protein, with retinoic acid receptor and STAT3 signaling
pathways.
SO - Blood 2002 Apr 15;99(8):2637-46
AD - Section of Infectious Disease, Department of Medicine, Baylor College of
Medicine, Houston, TX 77030, USA.
Signal transducer and activator of transcription (STAT) 5b-retinoic acid
receptor (RAR) alpha is the fifth fusion protein identified in acute
promyelocytic leukemia (APL). Initially described in a patient with
all-trans retinoic acid (ATRA)-unresponsive disease, STAT5b-RARalpha
resulted from an interstitial deletion on chromosome 17. To determine
the molecular mechanisms of myeloid leukemogenesis and maturation arrest
in STAT5b-RARalpha(+) APL and its unresponsiveness to ATRA, we examined
the effect of STAT5b-RARalpha on the activity of myeloid transcription
factors including RARalpha/retinoid X receptor (RXR) alpha, STAT3, and
STAT5 as well as its molecular interactions with the nuclear receptor
corepressor, SMRT, and nuclear receptor coactivator, TRAM-1.
STAT5b-RARalpha bound to retinoic acid response elements (RAREs) both as
a homodimer and as a heterodimer with RXRalpha and inhibited wild-type
RARalpha/RXRalpha transactivation. Although STAT5b-RARalpha had no
effect on ligand-induced STAT5b activation, it enhanced interleukin
6-induced STAT3-dependent reporter activity, an effect shared by other
APL fusion proteins including promyelocytic leukemia-RARalpha and
promyelocytic leukemia zinc finger (PLZF)-RARalpha. SMRT was released
from STAT5b-RARalpha/SMRT complexes by ATRA at 10(-6) M, whereas TRAM-1
became associated with STAT5b-RARalpha at 10(-7) M. The coiled-coil
domain of STAT5b was required for formation of STAT5b-RARalpha
homodimers, for the inhibition of RARalpha/RXRalpha transcriptional
activity, and for stability of the STAT5b-RARalpha/SMRT complex. Thus,
STAT5b-RARalpha contributes to myeloid maturation arrest by binding to
RARE as either a homodimer or as a heterodimer with RXRalpha resulting
in the recruitment of SMRT and inhibition of RARalpha/RXRalpha
transcriptional activity. In addition, STAT5b-RARalpha and other APL
fusion proteins may contribute to leukemogenesis by interaction with the
STAT3 oncogene pathway.
8
UI - 11960906
AU - Kuerbitz SJ; Pahys J; Wilson A; Compitello N; Gray TA
TI -
Hypermethylation of the imprinted NNAT locus occurs frequently in
pediatric acute leukemia.
SO - Carcinogenesis 2002 Apr;23(4):559-64
AD - Department of Pediatrics and Department of Genetics, Case Western
Reserve University and Ireland Cancer Center, Cleveland, OH 44109, USA.
Recent studies have demonstrated imprinting of the human neuronatin
(NNAT) gene. NNAT maps to 20q11.2-q12, a region exhibiting loss of
heterozygosity in acute myeloid leukemia and
myelodysplastic/myeloproliferative disease. To investigate possible
epigenetic dysregulation of genes in this region relevant to
leukemogenesis, we analyzed methylation of the NNAT gene in normal
tissues and in leukemias. We found a differential methylation pattern,
typical of imprinted genes, at sites in the CpG island containing NNAT
exon 1 in normal pituitary, peripheral blood cells and bone
marrow-derived CD34-positive hematopoietic progenitor cells. Substantial
or complete loss of the unmethylated NNAT allele was observed in
leukemia cell lines and in 20 of 29 (69%) acute myeloid or lymphoid
leukemia samples. While most highly expressed in brain, NNAT mRNA was
also detected in normal hematopoietic progenitor cells and in leukemia
cells exhibiting the normal methylation pattern, although not in
hypermethylated leukemia cells. Demethylation by treatment of
hypermethylated leukemia cells with 5-aza-2'-deoxycytidine resulted in
reactivation of NNAT expression, concomitant with a reversion to the
normal methylation pattern. The data demonstrate that hypermethylation
of the NNAT locus is a frequent event in both myeloid and lymphoid acute
leukemias of childhood. Aberrant hypermethylation of the NNAT locus
suggests that the dysregulation of genes at 20q11.2-q12 in leukemia may
be the result of epigenetic as well as genetic events.
9
UI - 12020434
AU - Little MP
TI -
Comments on the paper: Microsatellite instability in acute myelocytic
leukaemia developed from A-bomb survivors.
SO - Int J Radiat Biol 2002 May;78(5):441-3
10
UI - 12025826
AU - Cox R; Edwards AA
TI -
Comments on the paper: Microsatellite instability in acute myelocytic
leukaemia developed from A-bomb survivors--and related cytogenic data.
SO - Int J Radiat Biol 2002 May;78(5):443-5
11
UI - 11986943
AU - Pendino F; Sahraoui T; Lanotte M; Segal-Bendirdjian E
TI -
A novel mechanism of retinoic acid resistance in acute promyelocytic
leukemia cells through a defective pathway in telomerase regulation.
SO - Leukemia 2002 May;16(5):826-32
AD - INSERM U496, Centre G Hayem, Hopital Saint-Louis, 1 Avenue Claude
Vellefaux, 75010 Paris, France.
Human telomerase, a cellular reverse transcriptase specifically
activated in most malignant tumors and usually inactive in normal
somatic cells, plays an important role in immortalization and
tumorigenesis. Early reports have indicated that terminal
differentiation of various cells is associated with a rapid inhibition
of telomerase activity, preceded by a down-regulation of telomerase
reverse transcriptase (hTERT) mRNA. Recently, we have shown that
telomerase can be repressed by all-trans retinoic acid (ATRA)
independently of terminal maturation during long-term ATRA treatment of
the maturation-resistant promyelocytic leukemia cell line (NB4-R1),
leading to shortening of telomeres and cell death, events overcome by
ectopic hTERT expression. Here, we report the isolation of a variant of
NB4-R1 cells (NB4-R1(SFD)), which bypasses this death step, because of a
re-activated telomerase, despite the continuous presence of ATRA. While
unresponsive to a long-term maturation independent regulation of
telomerase by ATRA, these cells retain a functional pathway of
telomerase down-regulation associated with retinoid-induced maturation.
These findings reinforce the notion that two distinct pathways of
telomerase regulation by retinoids co-exist in APL cells. Noteworthy, we
show that the slow developing mechanism, that causes death of
maturation-resistant cells, is subjected to a new type of
retinoid-resistance as yet not understood.
12
UI - 11964319
AU - Milella M; Estrov Z; Kornblau SM; Carter BZ; Konopleva M; Tari A;
TI -
Schober WD; Harris D; Leysath CE; Lopez-Berestein G; Huang Z; Andreeff M
Synergistic induction of apoptosis by simultaneous disruption of the
Bcl-2 and MEK/MAPK pathways in acute myelogenous leukemia.
SO - Blood 2002 May 1;99(9):3461-4
AD - Department of Blood and Marrow Transplantation, Section of Molecular
Hematology and Therapy, The University of Texas M. D. Anderson Cancer
Center, Houston, TX 77030, USA.
Recent studies suggest that the Bcl-2 and mitogen-activated protein
kinase (MAPK) pathways together confer an aggressive,
apoptosis-resistant phenotype on acute myelogenous leukemia (AML) cells.
In this study, we analyzed the effects of simultaneous inhibition of
these 2 pathways. In AML cell lines with constitutively activated MAPK,
MAPK kinase (MEK) blockade by PD184352 strikingly potentiated the
apoptosis induced by the small-molecule Bcl-2 inhibitor HA14-1 or by
Bcl-2 antisense oligonucleotides. Isobologram analysis confirmed the
synergistic nature of this interaction. Moreover, MEK blockade overcame
Bcl-2 overexpression-mediated resistance to the proapoptotic effects of
HA14-1. Most importantly, simultaneous exposure to PD184352
significantly (P =.01) potentiated HA14-1-mediated inhibition of
clonogenic growth in all primary AML samples tested. These findings show
that the Bcl-2 and MAPK pathways are relevant molecular targets in AML
and that their concurrent inhibition could be developed into a new
therapeutic strategy for this disease.
13
UI - 12040453
AU - Rex JH; Anaissie EJ; Boutati E; Estey E; Kantarjian H
TI -
Systemic antifungal prophylaxis reduces invasive fungal in acute
myelogenous leukemia: a retrospective review of 833 episodes of
neutropenia in 322 adults.
SO - Leukemia 2002 Jun;16(6):1197-9
14
UI - 11921274
AU - Block AW; Carroll AJ; Hagemeijer A; Michaux L; van Lom K; Olney HJ; Baer
TI -
MR
Rare recurring balanced chromosome abnormalities in therapy-related
myelodysplastic syndromes and acute leukemia: report from an
international workshop.
SO - Genes Chromosomes Cancer 2002 Apr;33(4):401-12
AD - Clinical Cytogenetics Laboratory, Roswell Park Cancer Institute,
Buffalo, New York 14263, USA. annemarie.block@roswellpark.org
Seventy-seven patients were identified with Rare recurring (excluding
11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511
patients with treatment-related myelodysplastic syndromes and acute
leukemia accepted from centers in the United States, Europe, and Japan.
The abnormality subsets included 3q21q26 (17 patients), 11p15 (17
patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients),
t(8;16)(p11;p13) (9 patients), and an "other" subset, which included
t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3
patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients),
t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and
t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with
additional balanced and unbalanced rearrangements was observed in 70% of
cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or
7 abnormalities were observed in 59%. The most frequent primary diseases
were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin
lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients
received alkylating agents plus topoisomerase II inhibitors with or
without radiation therapy. The presenting diagnosis was t-AML in 47
cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven
cases, five of whom had a t(9;22). The median latency time from
initiation of original therapy to therapy-related disease diagnosis was
quite long (69 months), and the overall median survival from the date of
therapy-related disease diagnosis was very short (7 months). The 1-year
survival rate was 34 +/- 7%, with no significant differences among
subsets. Comparison with previously reported cases showed increased
karyotypic complexity and adult presentation of pediatric-associated
chromosome abnormalities. Copyright 2002 Wiley-Liss, Inc.
15
UI - 11911810
AU - Lamothe B; Aggarwal BB
TI -
Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by
TNF-related apoptosis-inducing ligand (TRAIL) through suppression of
caspases-8, 7, and 3 and BID cleavage in human acute myelogenous
leukemia cell line HL-60.
SO - J Interferon Cytokine Res 2002 Feb;22(2):269-79
AD - Cytokine Research Section, Department of Bioimmunotherapy, The
University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009,
USA.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is
one of the latest members of the TNF superfamily known to induce
apoptosis in a wide variety of tumor cells. Some cell types, however,
are quite resistant to TRAIL. We investigated the effect of ectopic
expression of Bcl-2 and Bcl-xL on TRAIL-induced apoptosis in human acute
myelogenous leukemia HL-60 cells. We found that HL-60 cells, which
express TRAIL receptors (also called death receptor, DR) DR4, DR5, and
Dc (decoy) R2, are highly sensitive to TRAIL-induced cytotoxicity.
Greater than 90% killing occurred within 24 h of TRAIL treatment. The
expression of Bcl-2 and Bcl-xL, however, completely abolished the
TRAIL-induced cytotoxic effects. Treatment of HL-60 cells with TRAIL
induced caspase-8 activation within 2-4 h, but no activation could be
seen in Bcl-2-expressing or Bcl-xL-expressing cells. TRAIL also induced
cleavage of BID, which was also abolished by Bcl-2 and Bcl-xL.
Similarly, TRAIL activated caspase-3 and caspase-7 in control cells but
not in cells expressing Bcl-2 or Bcl-xL. Cleavage of the caspase-3
substrate poly(ADP-ribose) polymerase (PARP), was abrogated by ectopic
expression of Bcl-2 and Bcl-xL. Inhibition of caspases by the
pan-caspase inhibitor,
benzyloxycarbonyl-valine-alanine-aspartate-fluoromethylketone (zVAD-fmk)
abolished the TRAIL-induced apoptosis. Overall, these results indicate
that TRAIL-induced apoptosis involves activation of caspase-8,
caspase-7, caspase-3, and BID cleavage, and Bcl-2 and Bcl-xL prevents
TRAIL-induced apoptosis by abrogating caspase activation and BID
cleavage.
16
UI - 11920269
AU - Gu BW; Hu J; Xu L; Yan H; Jin WR; Zhu YM; Zhao WL; Niu C; Cao Q; Su XY;
TI -
Gu J; Ying HY; Chen Y; Xiong SM; Shen ZX; Chen Z; Chen SJ
Feasibility and clinical significance of real-time quantitative RT-PCR
assay of PML-RARalpha fusion transcript in patients with acute
promyelocytic leukemia.
SO - Hematol J 2001;2(5):330-40
AD - Shanghai Institute of Hematology, Key Laboratory of Human Genome
Research, Ministry of Public Health and Shanghai Municipality, Rui-Jin
Hospital, Shanghai Second Medical University, 197 Rui Jin Road II,
Shanghai 200025, P.R. China.
INTRODUCTION: To study the relationship between the expression level of
the PML-RARalpha fusion transcripts and the clinical status and
efficiency of the therapy in acute promyelocytic leukemia (APL)
patients, we applied a very sensitive and specific real-time Reverse
Transcription Polymerase Chain Reaction (RT-PCR) system to quantify the
dose of PML-RARalpha fusion transcripts in a series of APL patients at
distinct disease stages. MATERIALS AND METHODS: A total of 31 APL
patients (19 males and 12 females; aged from 8 to 74 years) from eight
hospitals in Shanghai were analysed. Real-time Quantitative RT-PCR was
used to measure the normalized dose (DoseN) of PML-RARalpha fusion
transcripts. RESULTS: A wide range of PML-RARalpha DoseN above 1 x 10(3)
was noted in 25 newly diagnosed patients. PML-RARalpha DoseN was
significantly decreased after remission induction with ATRA,
ATRA/chemotherapy or As2O3 and further reduced after consolidation. The
fact that all patients with long disease free survival had a constantly
low PML-RARalpha DoseN below 2 x 10(2) and a higher level predicted
impending relapse suggests that this value could serve as a 'threshold'
for molecular remission. PML-RARalpha DoseN was also of prognostic value
in a group of relapsed patients, since good response to As2O3
reinduction was accompanied by a remarkable reduction of fusion
transcript level, whereas patients with high PML-RARalpha Dose(N) after
the second CR tended to relapse again rapidly. CONCLUSION: These results
confirm that real-time RT-PCR assay for PML-RARalpha transcripts in APL
patients is useful in reflecting leukemic burden, assessing response to
treatment and indicating the ultimate clinical outcome or curability of
disease.
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