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NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of AML - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
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.
2
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.
3
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. inokuchi@nms.ac.jp
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.
4
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. sse@dne.unife.it
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.
5
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.
6
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.
7
UI - 11568912
AU - Eguchi M; Eguchi-Ishimae M
TI -
Absence of t(12;15) associated ETV6-NTRK3 fusion transcripts in
pediatric acute leukemias.
SO - Med Pediatr Oncol 2001 Oct;37(4):417
8
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. iboll@rios.de
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
9
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. maeguchi@icr.ac.uk
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.
10
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.
11
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.
12
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.
13
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.
14
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.
15
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.
16
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.
17
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. jurcicj@mskcc.org
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.
18
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.
19
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. kajsa.paulsson@klingen.lu.se
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.
20
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. dstirewa@fhcrc.org
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.
21
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.
22
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.
23
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.
a.zelent@icr.ac.uk
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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