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NCI CANCERLIT® Search: Diagnosis-Histopathology-Pathogenesis of AML - October 2002
National Cancer Institute®
Last Modified: October 1, 2002
- [Expression of NM23-H(1) mRNA in acute leukemia]
- Bone marrow reticulin fibrosis at diagnosis in promyelocytic leukaemia treated with all-trans retinoic acid has no adverse prognosis.
- Cancer epigenetics and methylation.
- Serum immunoglobulins to endotoxin core glycolipid: acute leukaemia and other cancers.
- Lack of correlation between growth of TF-1 cells and tyrosine phosphorylation signals in response to IL-3, IL-5 and GM-CSF.
- [Cell differentiation and apoptosis of tumor cells]
- Mitochondrial membrane sensitivity to depolarization in acute myeloblastic leukemia is associated with spontaneous in vitro apoptosis,
- [Invasive aspergillosis in the leukemic patient]
- [Pilot study of PML/RAR alpha fusion by fluorescence in situ hybridization (FISH)method in acute promyelocyte leukemia]
- Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience.
- Differential gene expression in retinoic acid-induced differentiation of acute promyelocytic leukemia cells, NB4 and HL-60 cells.
- Spotlight on acute promyelocytic leukemia: controversies and challenges.
- PML a target of translocations in APL is a regulator of cellular senescence.
- Variations on a theme: the alternate translocations in APL.
- Retinoic acid resistance in acute promyelocytic leukemia.
- Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment
- Inhibition of the transforming activity of FLT3 internal tandem duplication mutants from AML patients by a tyrosine kinase inhibitor.
- Quantitative assessment of WT1 expression by real time quantitative PCR may be a useful tool for monitoring minimal residual disease in acute
- [The relationship between expression of lung resistance-related protein gene or multidrug resistance-associated protein gene and prognosis in
- Study on P16 gene in acute leukemia.
- The coagulopathy of acute promyelocytic leukemia.
- [Acute myeloblastic leukemia with involvement of the basophilic cell line and anomalies of the short arm of chromosome 12 (12p)]
- Alterations of the putative tumor suppressor gene p16/MTS1 in human hematological malignancies.
Table of Contents
1
UI - 12137595
AU - Wu S; Zhao C
TI -
[Expression of NM23-H(1) mRNA in acute leukemia]
SO - Zhonghua Nei Ke Za Zhi 2002 Jun;41(6):367-9
AD - Department of Hematology, The Affiliated Hospital of Qingdao University
Medical College, Qingdao 266003, China.
OBJECTIVE: To determine the expression of NM23-H(1) gene in acute
leukemia(AL) and evaluate the relationship between NM23-H(1) expression
and clinical features. METHODS: Expression level of NM23-H(1) mRNA in
bone marrow cells was determined in 82 acute leukemia patients and 15
normal subjects with semi-quantitative reverse transcription polymerase
chain reaction(RT-PCR). RESULTS: NM23-H(1)/ GAP DH ratio >/= 0.5 was
considered to be positive. NM23-H(1) mRNA was negative in all the 15
normal subjects. Expression of NM23-H(1) was positive in 43 of the 56
acute leukemia patients in the first visit, expression range being 0.33
approximately 2.75. There was one positive case in 12 AL patients with
complete remission, expression range being 0 approximately 0.63,but
there was no positive case in 6 AL patients who had maintained complete
remission for more than 6 months, expression range being 0 approximately
0.27. Relapsed cases were all positive with an expression range of 0.76
approximately 1.87. NM23-H(1) expression in patients with initial and
relapsed acute leukemia was higher than that in normal subjects (P <
0.01). CONCLUSION: Overexpression of NM23-H(1) mRNA can predict
treatment outcome and may be an important prognostic factor.
2
UI - 12187033
AU - Losada R; Cabrera H; Hernandez P; Hernandez C; Menendez A; Mesa J;
TI -
Plascencia A; Ramon L; Agramonte O; Espinosa E
Bone marrow reticulin fibrosis at diagnosis in promyelocytic leukaemia
treated with all-trans retinoic acid has no adverse prognosis.
SO - Acta Haematol 2002;108(2):111-2
AD - Instituto de Hematologia e Inmunologia, La Habana, Cuba.
ihidir@hemato.sld.cu
3
UI - 12229925
AU - Esteller M; Fraga MF; Paz MF; Campo E; Colomer D; Novo FJ; Calasanz MJ;
TI -
Galm O; Guo M; Benitez J; Herman JG
Cancer epigenetics and methylation.
SO - Science 2002 Sep 13;297(5588):1807-8; discussion 1807-8
4
UI - 2386384
AU - Jackson SK; Parton J; Shortland G; Stark JM; Thompson EN
TI -
Serum immunoglobulins to endotoxin core glycolipid: acute leukaemia and
other cancers.
SO - Arch Dis Child 1990 Jul;65(7):771-3
AD - University of Wales College of Medicine, Heath Park, Cardiff.
Circulating antibody to endotoxin core glycolipid and total serum
immunoglobulin concentrations were measured in 86 children with cancer
(54 with acute lymphoblastic leukaemia, four with acute myeloid
leukaemia, and 28 with various solid tumours). Measurements were made
before treatment in the group with acute lymphoblastic leukaemia as well
as when patients were both on and off chemotherapy. In the other two
groups measurements were made when patients were both on and off
treatment. Significant reductions in endotoxin antibody and serum
immunoglobulin concentrations were found only in patients with acute
lymphoblastic leukaemia. In addition, there was a significant
correlation between febrile episodes and the concentration of antibody
to core glycolipid in the children with acute lymphoblastic leukaemia.
These findings suggest that the use of prophylactic high titre endotoxin
antibody may be of benefit to children with life threatening Gram
negative infections who are receiving cytotoxic chemotherapy.
5
UI - 9325013
AU - Ettinger S; Fong D; Duronio V
TI -
Lack of correlation between growth of TF-1 cells and tyrosine
phosphorylation signals in response to IL-3, IL-5 and GM-CSF.
SO - Cytokine 1997 Sep;9(9):650-9
AD - Department of Medicine, University of British Columbia, Jack Bell
Research Centre, Vancouver, Canada.
The human cell line, TF-1, was used to compare responses to interleukin
3 (IL-3), IL-5 and granulocyte-macrophage colony-stimulating factor
(GM-CSF). TF-1 cells grew well in the presence of any one of the
cytokines in early passages. However, the level of tyrosine
phosphorylation was minimal in response to IL-5, and detection of a
tyrosine phosphorylation signal required high concentrations of IL-5.
When grown for longer periods of time in the presence of one of the
cytokines, there were dramatic difference in the cells' responses. IL-3
or GM-CSF-grown cells showed only half of the original bioassay response
to IL-5. However, cells grown in IL-5 alone kept the same response, and
all cells showed the same response to IL-3 and GM-CSF. IL-5-grown cells
also had an increased tyrosine phosphorylation signal, along with
increased sensitivity to IL-5, yet there was no difference in an IL-5
bioassay. The relative level of detection of tyrosine phosphorylated
JAK-2, STAT-5, SHC, and other substrates corresponded to the overall
tyrosine phosphorylation signal. IL-5-grown cells had approximately
10-fold more IL-5 receptor alpha subunit message compared to IL-3-grown.
These results suggest that response of TF-1 cells to IL-5 may be
deceiving in that a good response in a bioassay can be observed with
relatively little tyrosine phosphorylation, but an increase in tyrosine
phosphorylation can be correlated with an increase in the expression of
IL-5 receptor alpha subunit.
6
UI - 11783236
AU - Zhang T
TI -
[Cell differentiation and apoptosis of tumor cells]
SO - Zhongguo Zhong Xi Yi Jie He Za Zhi 1999 May;19(5):261-2
7
UI - 11435310
AU - Pallis M; Grundy M; Turzanski J; Kofler R; Russell N
TI -
Mitochondrial membrane sensitivity to depolarization in acute
myeloblastic leukemia is associated with spontaneous in vitro apoptosis,
wild-type TP53, and vicinal thiol/disulfide status.
SO - Blood 2001 Jul 15;98(2):405-13
AD - Division of Haematology, University of Nottingham and Nottingham City
Hospital, United Kingdom.
Nonresponse to remission-induction chemotherapy, which remains a major
problem in acute myeloblastic leukemia (AML), has been linked to
cellular resistance to apoptosis. Because the apoptosis induced by
chemotherapeutic drugs is mediated by loss of mitochondrial
transmembrane potential (MTP), it was postulated that sensitivity to
mitochondrial membrane depolarization might be heterogeneous in AML.
Using the uncoupling agent carbonyl cyanide m-chlorophenylhydrazone
(mClCCP), the mitochondrial membrane sensitivity to depolarization
(mClCCP concentrations that inhibit 50% of the transmembrane potential
[IC(50)]) in AML blasts was measured and demonstrated marked interclonal
heterogeneity, with the existence of comparatively sensitive (median
mClCCP IC(50), 4 microM) and resistant (median mClCCP IC(50), 10 microM)
clones. Furthermore, the mClCCP IC(50) was inversely associated with
spontaneous in vitro apoptosis (P =.001). It was high in cases with
mutant TP53 and correlated with the total cellular level of the
multidrug resistance-associated protein (P =.019) but not of bcl-2, bax,
or bcl-x. It was also found that the dithiol oxidant diamide, in
contrast to the monovalent thiol oxidant diethyl maleate, increased the
sensitivity of mitochondrial membranes to mClCCP. To confirm that TP53
directly affects MTP in leukemic cells and to establish the role of
vicinal thiol oxidation in the TP53-dependent pathway, CEM 4G5 leukemia
cells with forced, temperature-dependent expression of TP53 were
studied. Monobromobimane, which inhibits mitochondrial membrane
depolarization by preventing dithiol cross-linking, inhibited
depolarization and apoptosis in 4G5 cells. It was concluded that in
leukemia, TP53 and vicinal thiol/disulfide status are determinants of
mitochondrial membrane sensitivity to depolarization, which is in turn
associated with spontaneous apoptosis.
8
UI - 11924181
AU - el Omri H; Mili-Fathallah A; Amara H; Ben Youssef Y; Garrouche A; Ben
TI -
Said M; Ennabli S
[Invasive aspergillosis in the leukemic patient]
SO - Rev Mal Respir 2001 Dec;18(6 Pt 1):607-14
AD - Service d'Hematologie Clinique, CHU Farhat Hached, 4000 Sousse, Tunisie.
Invasive pulmonary aspergillosis (IPA) remains a life threatening
complication in immuno-compromised and especially in neutropenic
patients. We report our experience in the diagnosis and therapeutic
management of IPA in 8 patients with acute leukemia. All patients were
neutropenic (PNN < 100/mm3, mean duration = 37 days) when IPA was
diagnosed. Clinical signs included fever above 39 degrees and cough in
all cases, chest pain in 4 cases, hemoptysis in 3 cases, rales in 5
cases. Chest x ray showed one lesion in 4 cases and multiple lesions in
4 cases. The diagnosis of IPA was established by bronchoalveolar lavage
(BAL) in 5 cases, tissue biopsy in one case, positive sputum in one case
and it was highly probable in one case. Thoracic computed tomographic
(CT) scans were preformed after diagnosis confirmation of IPA and showed
one or multiple lesions with air crescent signs. Serological tests were
positive in 4 cases late in the course of IPA. All patients were treated
with i.v. Amphotericin B. Outcome was favorable in 5 cases and three
patients died by massive hemoptysis (in two cases) and systemic
aspergillosis (in one case). Early diagnosis and appropriate treatment
are essential to improve IPA prognosis.
9
UI - 12235897
AU - Legues ME; Franco G; Bertin P
TI -
[Pilot study of PML/RAR alpha fusion by fluorescence in situ
hybridization (FISH)method in acute promyelocyte leukemia]
SO - Rev Med Chil 2002 Jul;130(7):737-44
AD - Laboratorio de Hematologia, Departamento de Hematologia-Oncologia,
Pontificia Universidad Catolica de Chile, Lira 44, Santiago.
BACKGROUND: Acute promyelocytic leukemia (APL) is characterized
cytogenetically by t(15;17) (q22;q21) and its molecular consequence,
fusion of PML and RAR alpha genes. The detection of this genetic marker
confirms the diagnosis and allows monitoring of the leukemic clone
during treatment, which has prognostic value. Cytogenetics fails in some
cases due to the absence of metaphases in cultures or their bad
morphology. Southern blot and PCR methods require trained personnel and
adequate equipment. FISH method allows the identification of chromosomic
rearrangements in 24 to 48 h and is simple to set up in a cytogenetics
laboratory. AIM: To evaluate the FISH method to detect PML/RAR alpha
fusion, compared to cytogenetic analysis. PATIENTS AND METHODS: Fifteen
bone marrow specimens from APL patients with previous cytogenetic
analysis were studied, using a commercial probe to detect PML/RAR alpha
fusion. RESULTS: We obtained a normal cut-off value of 9.1%. Specificity
and sensibility were 100%. Six positive cytogenetic cases at diagnosis
were FISH positive. Six negative cytogenetic cases, one APL at diagnosis
and five normal controls were FISH negative. One case in remission, that
was negative by cytogenetics, was positive near the cut-off value by
FISH. Two other cases in remission, not conclusive by cytogenetics, were
negative by FISH. CONCLUSIONS: FISH is a reliable, rapid and relatively
low cost method that can be used as an adjunct to conventional
cytogenetics.
10
UI - 12200354
AU - Pulsoni A; Pagano L; Lo Coco F; Avvisati G; Mele L; Di Bona E;
TI -
Invernizzi R; Leoni F; Marmont F; Mele A; Melillo L; Nosari AM; Pogliani
EM; Vignetti M; Visani G; Zagonel V; Leone G; Mandelli F
Clinicobiological features and outcome of acute promyelocytic leukemia
occurring as a second tumor: the GIMEMA experience.
SO - Blood 2002 Sep 15;100(6):1972-6
AD - Cellular Biotechnology and Hematology Department, La Sapienza
University, Via Benevento 6, 00161 Rome, Italy. pulsoni@bce.uniroma1.it
We analyzed the clinicobiological features and treatment outcome of a
series of acute promyelocytic leukemias (APLs) occurring as a second
tumor (APL-st's, n = 51) and compared these with a large group of de
novo APL cases (n = 641), both observed by the Italian cooperative group
GIMEMA. In the APL-st group, 37 patients had received radiotherapy
and/or chemotherapy for their primary malignancy (PM), while 14 had been
treated by surgery alone. Compared with de novo APL patients, APL-st
patients were characterized by a predominance of females (P <.003),
higher median age (P <.05), and worse performance status (P <.005). The
median time elapsed between PM and APL-st was 36 months, with a longer
latency for patients treated with surgery alone. No significant
differences were found with regard to karyotypic lesions or type of
promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha)
fusion in the 2 cohorts. A high prevalence of PMs of the reproductive
system was observed among the female APL-st population (24 [71%] of 34
patients in this group had suffered from breast, uterine, or ovarian
cancer). Thirty-one APL-st and 641 de novo APL patients received
homogeneous APL therapy according to the all-trans retinoic acid (ATRA)
and idarubicin regimen (the AIDA regimen). The complete remission (CR),
4-year event-free survival (EFS), and 4-year overall survival (OS) rates
were 97% and 93%, 65% and 68%, and 85% and 78% in the APL-st and de novo
APL groups, respectively. In spite of important clinical differences
(older age and poorer performance status), the APL-st group responded as
well as the de novo APL group to upfront ATRA plus chemotherapy,
probably reflecting genetic similarity.
11
UI - 12207890
AU - Lee KH; Chang MY; Ahn JI; Yu DH; Jung SS; Choi JH; Noh YH; Lee YS; Ahn
TI -
MJ
Differential gene expression in retinoic acid-induced differentiation of
acute promyelocytic leukemia cells, NB4 and HL-60 cells.
SO - Biochem Biophys Res Commun 2002 Sep 6;296(5):1125-33
AD - Department of Biochemistry, College of Medicine, Hanyang University,
Seoul, Republic of Korea.
Acute promyelocytic leukemia (APL) is characterized by a specific
chromosome translocation t(15;17), which results in the fusion of the
promyelocytic leukemia gene (PML) and retinoic acid receptor alpha gene
(RARalpha). APL can be effectively treated with the cell differentiation
inducer all-trans retinoic acid (ATRA). NB4 cells, an acute
promyelocytic leukemia cell line, have the t(15;17) translocation and
differentiate in response to ATRA, whereas HL-60 cells lack this
chromosomal translocation, even after differentiation by ATRA. To
identify changes in the gene expression patterns of promyelocytic
leukemia cells during differentiation, we compared the gene expression
profiles in NB4 and HL-60 cells with and without ATRA treatment using a
cDNA microarray containing 10,000 human genes. NB4 and HL-60 cells were
treated with ATRA (10(-6)M) and total RNA was extracted at various time
points (3, 8, 12, 24, and 48h). Cell differentiation was evaluated for
cell morphology changes and CD11b expression. PML/RARalpha degradation
was studied by indirect immunofluoresence with polyclonal PML
antibodies. Typical morphologic and immunophenotypic changes after ATRA
treatment were observed both in NB4 and HL-60 cells. The cDNA microarray
identified 119 genes that were up-regulated and 17 genes that were
down-regulated in NB4 cells, while 35 genes were up-regulated and 36
genes were down-regulated in HL60 cells. Interestingly, we did not find
any common gene expression profiles regulated by ATRA in NB4 and HL-60
cells, even though the granulocytic differentiation induced by ATRA was
observed in both cell lines. These findings suggest that the molecular
mechanisms and genes involved in ATRA-induced differentiation of APL
cells may be different and cell type specific. Further studies will be
needed to define the important molecular pathways involved in
granulocytic differentiation by ATRA in APL cells.
12
UI - 12357340
AU - Melnick A
TI -
Spotlight on acute promyelocytic leukemia: controversies and challenges.
SO - Leukemia 2002 Oct;16(10):1893-5
AD - Department of Developmental and Molecular Biology and Albert Einstein
Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461,
USA.
13
UI - 12357343
AU - Ferbeyre G
TI -
PML a target of translocations in APL is a regulator of cellular
senescence.
SO - Leukemia 2002 Oct;16(10):1918-26
AD - Universite de Montreal, Departement de Biochimie, Canada.
PML is the most frequent fusion partner of the RARalpha in the specific
translocations associated with acute promyelocytic leukemia (APL).
Models to explain the origin of this leukemia propose a block in cell
differentiation due to aberrant repression of retinoic acid responsive
genes and/or disruption of the function of the PML-containing nuclear
bodies. Recently, PML has been identified as a regulator of replicative
senescence and the premature senescence that occurs in response to
oncogenic ras. This review discusses the idea that senescence is a
general tumor suppressor mechanism related to terminal differentiation
and disrupted during the establishment of APL and other cancers.
According to this idea the PML-RARalpha fusion protein promotes
leukemogenesis not only through repression of retinoic acid responsive
genes, but also by way of interfering with several tumor suppressor
proteins that cooperate to establish senescence. Retinoids and other
drugs effective against APL do so by re-establishment of the senescence
program, which also includes features of cell differentiation.
14
UI - 12357344
AU - Redner RL
TI -
Variations on a theme: the alternate translocations in APL.
SO - Leukemia 2002 Oct;16(10):1927-32
AD - Department of Medicine, University of Pittsburgh, PA 15213, USA.
The t(15;17)(q22;q21) translocation is tightly linked to the APL
phenotype, and the resultant PML-RAR fusion can be demonstrated in 98%
of APL cases. Rare variant translocations have been reported, the
majority of which on detailed analysis represent cryptic PML-RAR
fusions. However, a handful of APL cases have been described with
different genotypes. These include the t(11;17)(q23;q21) that produces
the PLZF-RAR fusion, t(5;17)(q35;q21) that forms NPM-RAR,
t(11;17)(q13;q21) that generates NUMA-RAR, and der(17) that creates
STAT5b-RAR. In this review we will discuss these variant translocations,
and discuss the insights that we have gained from their study.
15
UI - 12357346
AU - Gallagher RE
TI -
Retinoic acid resistance in acute promyelocytic leukemia.
SO - Leukemia 2002 Oct;16(10):1940-58
AD - Department of Oncology, Montefiore Medical Center, New York 10467, USA.
Primary resistance of PML-RARalpha-positive acute promyelocytic leukemia
(APL) to the induction of clinical remission (CR) by all-trans retinoic
acid (ATRA) is rare but markedly increases in frequency after > or =2
relapses from chemotherapy-induced CRs. Nevertheless, even in de novo
cases, the primary response of ATRA-naive cases is variable by several
measures, suggesting involvement of heterogeneous molecular elements.
Secondary, acquired ATRA resistance occurs in most patients treated with
ATRA alone and in many patients who relapse from combination ATRA
chemotherapy regimens despite limited ATRA exposure. Although early
studies suggested that an adaptive hypercatabolic response to
pharmacological ATRA levels is the principal mechanism of ATRA
resistance, recent studies suggest that molecular disturbances in APL
cells have a predominant role, particularly if disease relapse occurs a
few months after discontinuing ATRA therapy. This review summarizes the
systemic and APL cellular elements that have been linked to clinical
ATRA resistance with emphasis on identifying areas of deficient
information and important topics for further investigation. Overall, the
subject review strongly supports the hypothesis that, although APL is an
infrequent and nearly cured disease, much can be gained by understanding
the complex relationship of ATRA resistance to the progression and
relapse of APL, which has important implications for other leukemias and
malignancies.
16
UI - 12357347
AU - Grimwade D; Lo Coco F
TI -
Acute promyelocytic leukemia: a model for the role of molecular
diagnosis and residual disease monitoring in directing treatment
approach in acute myeloid leukemia.
SO - Leukemia 2002 Oct;16(10):1959-73
AD - Division of Medical and Molecular Genetics, Guy's, King's and St Thomas'
School of Medicine, London, UK.
Acute promyelocytic leukemia (APL) is characterized by a number of
features that underpin the need for rapid and accurate diagnosis and
demand a highly specific treatment approach. These include the
potentially devastating coagulopathy, sensitivity to anthracycline-based
chemotherapy regimens, as well as unique responses to all-trans retinoic
acid and arsenic trioxide that have revolutionized therapy over the last
decade. The chromosomal translocation t(15;17) which generates the
PML-RARalpha fusion gene has long been considered the diagnostic
hallmark of APL; however, this abnormality is not detected in
approximately 10% cases with successful karyotype analysis. In the
majority of these cases, the PML-RARalpha fusion gene is still formed,
resulting from insertion events or more complex rearrangements. These
cases share the beneficial response to retinoids and favorable prognosis
of those with documented t(15;17), underscoring the clinical relevance
of molecular analyses in diagnostic refinement. In other cases of
t(15;17) negative APL, various chromosomal rearrangements involving
17q21 have been documented leading to fusion of RARalpha to alternative
partners, namely PLZF, NPM, NuMA and STAT5b. The nature of the fusion
partner has a significant bearing upon disease characteristics,
including sensitivity to retinoids and arsenic trioxide. APL has
provided an exciting treatment model for other forms of AML whereby
therapeutic approach is directed towards cytogenetically and molecularly
defined subgroups and further modified according to response as
determined by minimal residual disease (MRD) monitoring. Recent studies
suggest that rigorous MRD monitoring, coupled with pre-emptive therapy
at the point of molecular relapse improves survival in the relatively
small subgroup of PML-RARalpha positive patients with 'poor risk'
disease. Advent of 'real-time' quantitative RT-PCR technology seems set
to yield further improvements in the predictive value of MRD assessment,
achieve more rapid sample throughput and facilitate inter- and
intra-laboratory standardization, thereby enabling more reliable
comparison of data between international trial groups.
17
UI - 12357354
AU - Tse KF; Allebach J; Levis M; Smith BD; Bohmer FD; Small D
TI -
Inhibition of the transforming activity of FLT3 internal tandem
duplication mutants from AML patients by a tyrosine kinase inhibitor.
SO - Leukemia 2002 Oct;16(10):2027-36
AD - Johns Hopkins University School of Medicine, Department of Oncology
Baltimore, MD 21231, USA.
FLT3 is a receptor tyrosine kinase that may play a role in a significant
proportion of leukemias. In addition to being aberrantly expressed in
acute leukemias, activating mutations of the FLT3 gene have been found
in patients with AML, myelodysplastic syndrome (MDS) and more rarely,
ALL. Internal tandem duplications (ITDs) of the FLT3 gene have been
detected in 17-34% of patients with AML and portend a poor prognosis for
these patients. FLT3 receptors containing ITD mutations (FLT3/ITDs) are
constitutively activated in the absence of FLT3 ligand (FL) stimulation
leading to the activation of downstream signaling proteins, including
ERK and STAT 5. FLT3 activity, therefore, is a logical target for
therapeutic intervention. AG1296 is a tyrosine kinase inhibitor of the
tyrphostin class that shows inhibitory activity for wild-type FLT3, in
addition to the PDGF and c-KIT receptors. We examined the inhibitory
effects of AG1296 on FLT3/ITDs isolated from AML patients in the
IL-3-dependent cell line, Ba/F3, as well as in primary leukemia samples
from AML patients. Immunoprecipitation and immunoblotting analyses
demonstrated that FLT3/ITDs were constitutively phosphorylated in the
absence of FL. The auto-phosphorylation of FLT3/ITDs was inhibited by
AG1296 with an IC(50) of approximately 1 microM. FLT3/ITDs were
associated with constitutive phosphorylation of ERK, STAT 5A, STAT 5B,
CBL, VAV and SHP2 in Ba/F3 cells. The phosphorylation of these
downstream signaling molecules was suppressed in a dose-responsive
fashion by AG1296. AG1296 inhibited IL-3 independent growth and induced
apoptosis in Ba/F3 cells transformed by FLT3/ITDs. AG1296 also inhibited
FLT3 auto-phosphorylation, and induced a cytotoxic effect, in primary
AML cells. These findings suggest that inhibiting the activity of FLT3
may have a therapeutic value in some leukemias expressing FLT3/ITDs.
18
UI - 12357365
AU - Cilloni D; Gottardi E; De Micheli D; Serra A; Volpe G; Messa F;
TI -
Rege-Cambrin G; Guerrasio A; Divona M; Lo Coco F; Saglio G
Quantitative assessment of WT1 expression by real time quantitative PCR
may be a useful tool for monitoring minimal residual disease in acute
leukemia patients.
SO - Leukemia 2002 Oct;16(10):2115-21
AD - Division of Hematology and Internal Medicine, Dept of Clinical and
Biological Sciences of the University of Turin, Italy.
In order to verify if quantitative assessment of the WT1 transcript
amount by the real time quantitative PCR (RQ-PCR) can be used as a
marker for minimal residual disease detection, the WT1 transcript amount
was determined in BM and PB samples of patients with myeloid and
lymphoid acute leukemia, in normal controls, in regenerating bone marrow
samples and in purified CD34-positive cells from normal subjects. In 10
patients bearing a fusion gene transcript suitable for minimal residual
disease quantitative assessment, we performed a simultaneous analysis of
the WT1 and of the fusion-gene transcript at sequential time intervals
during follow-up. Sequential WT1 analysis was also performed in five AML
patients lacking additional molecular markers. The data obtained show
that normal and regenerating BM samples and purified CD34-positive cells
consistently express minimal amounts of WT1 transcript and that this is
extremely low and frequently undetectable in normal PB. By contrast,
high levels of WT1 expression are present in the BM and PB samples of
all acute leukemia (AL) cases at diagnosis. The WT1 levels during
follow-up were found to follow the pattern of the other molecular
markers (fusion gene transcripts) used for MRD monitoring and increased
WT1expression in the BM and/or PB during follow-up of AL patients was
always found to be predictive of an impending hematological relapse.
19
UI - 11940320
AU - Zhao Y; Yu L; Wang Q; Lou F; Pu J
TI -
[The relationship between expression of lung resistance-related protein
gene or multidrug resistance-associated protein gene and prognosis in
newly diagnosed acute leukemia]
SO - Zhonghua Nei Ke Za Zhi 2002 Mar;41(3):183-5
AD - Hematology Department, The General Hospital of PLA. Beijing 100853,
China.
OBJECTIVE: To evaluate the relationship between the expression of lung
resistance-related protein (lrp) gene or multidrug resistance-associated
protein (mrp) gene and prognosis in untreated acute leukemia (AL)
patients. METHODS: Reverse transcriptase-polymerase chain reaction
(RT-PCR) was used to examine the expression of lrp and mrp gene in 58
newly diagnosed AL patients. RESULTS: The positive rate of lrp and mrp
gene expression in newly diagnosed acute lymphocytic leukemia (ALL)
group was 15.0% and 40.0% and it was 15.8% and 42.1% in newly diagnosed
acute nonlymphocytic leukemia (ANLL) group. In both the ALL and ANLL
groups, the difference of the first complete remission rate in lrp
negative and in lrp positive patients was not significant (P > 0.05),
the same results were found with mrp gene. The difference of the first
complete remission rate between lrp(+)/mrp(+) and lrp(-)/mrp(-) patients
was significant (P < 0.05). There was no relationship between lrp and
mrp gene. CONCLUSION: Neither lrp nor mrp gene as a single indicator to
forecast original multidrug resistance is sensitive, but lrp combined
with mrp as one indicator will be sensitive.
20
UI - 11215050
AU - Chen Y; Zhang H; Yue B; Li H
TI -
Study on P16 gene in acute leukemia.
SO - J Tongji Med Univ 2000;20(3):210-1
AD - Institute of Hematology, Xiehe Hospital, Tongji Medical University,
Wuhan 430030.
To study the change of suppressing cancer gene P16 in acute leukemia,
the P16 antigen expression of leukemia cell surfaces in 61 cases were
investigated with ABC assay and gene structural defects in 51 cases of
acute leukemia were examined with multiple comparative PCR method. It
was found that antigen expression of P16 in leukemia was obviously lower
than that innormal subjects (P < 0.001). At the same time, antigen
expression in All was lower than that AML (P < 0.05). No significant
difference was found between the complete remission (CR) and
non-remission (NR) subjects from AML and ALL groups (P > 0.05). THe exon
2 of P16 gene showed homozygous deletion only inn 4 cases out of 30
cases in ALL. No structural defect was revealed in 21 cases of AML. It
was suggested that expression defect of P16 gene was a main cause in
development and progression of acute leukemia, and structural defect of
exon 2 was not a primary molecular event.
21
UI - 11990478
AU - Rodeghiero F
TI -
The coagulopathy of acute promyelocytic leukemia.
SO - Haemostasis 2001;31 Suppl 1():49-51
AD - Hematology Department, San Bortolo Hospital, Vicenza, Italy.
rodeghiero@hemato.ven.it
22
UI - 3928106
AU - Daniel MT; Bernheim A; Flandrin G; Berger R
TI -
[Acute myeloblastic leukemia with involvement of the basophilic cell
line and anomalies of the short arm of chromosome 12 (12p)]
SO - C R Acad Sci III 1985;301(6):299-301
Among 16 leukemia patients with abnormalities of the short arm of
chromosome 12 (12p) were found 5 patients with an increased number of
marrow basophils and a special M2 cytological feature. This new
correlation between 12p abnormalities and M2-baso phenotype is
presented. The localisation of c-k ras 2 genes at the same 12p site
suggests a possible mutation of this c-oncogene.
23
UI - 7882134
AU - Duro D; Flexor MA; Bernard O; d'Agay MF; Berger R; Larsen CJ
TI -
Alterations of the putative tumor suppressor gene p16/MTS1 in human
hematological malignancies.
SO - C R Acad Sci III 1994 Oct;317(10):913-9
AD - INSERM U301 et SDI n. 1954 I du CNRS, Institut de Genetique Moleculaire,
Paris, France.
The chromosome band 9p21-22 is frequently rearranged or deleted in a
variety of tumors including hematological malignancies. This supports
the notion of a tumor suppressor gene in this chromosome region. Indeed,
the p16/MTS1 gene encoding a cyclin-dependent kinase (CDK) inhibitor has
been shown to be frequently deleted and/or inactivated by nonsense
mutations in a number of tumors. We have examined 98 DNA samples from
blood, bone marrow cells and lymph node biopsies of patients with
leukemia (ALL and AML) or lymphoma (follicular lymphoma and T-cell
lymphoma), using Southern blot hybridization and a p16/MTS1-specific
probe. Molecular abnormalities, mainly homozygous deletions, were found
principally in ALL (8 out of 22 patients), much less frequently in AML
(2/32) and lymphoma (2/32). While these data argue in favor of a large
involvement of p16/MTS1 in ALL, AML and lymphomas appear to be less
frequently implicated.
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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