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NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of AML - August 2002
National Cancer Institute®
Last Modified: August 1, 2002
- The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid
- Diagnosis and molecular monitoring of acute promyelocytic leukemia using DzyNA reverse transcription-PCR to quantify PML/RARalpha fusion
- Cytogenetic, fluorescent in situ hybridization & reverse transcriptase-polymerase chain reaction analysis in acute promyelocytic
- A metal chelator, diphenylthiocarbazone, induces apoptosis in acute promyelocytic leukemia (APL) cells mediated by a caspase-dependent
- [Effects of all-trans retinoic acid and arsenic trioxide on tissue factor expression of acute promyelocytic leukemia cells]
- Comparison of outcome in acute myelogenous leukemia patients with translocation (8;21) found by standard cytogenetic analysis and patients
- Absence of mutations in the deoxycytidine kinase (dCK) gene in patients with relapsed and/or refractory acute myeloid leukemia (AML).
- Childbearing and the risk of leukemia in Sweden.
- Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Francais de Cytogenetique Hematologique
- Eliciting cytotoxic T lymphocytes against acute myeloid leukemia-derived antigens: evaluation of dendritic cell-leukemia cell hybrids and other
Table of Contents
1
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.
2
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. tapplega@medau.jnj.com
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.
3
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.
4
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.
5
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.
6
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.
7
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
8
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. karin.ekstrom@mep.ki.se
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.
9
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.
dastugue.n@chu-toulouse.fr
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.
10
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.
The above citations and abstracts reflect those newly added to CANCERLIT for the month and topic listed in the title. The citations have been retrieved from CANCERLIT using a predefined search strategy of indexed subject terms. Although the search strategy has been refined as best as possible, citations may appear that are not directly related to the topic, and occasionally relevant references may be omitted.
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