12th Congress of the European Hematology ... - Haematologica

efficacy and decreased atherosclerosis activity in patients with familial
hyperlipoproteinemia treated by extracorporeal LDL-cholesterol elimination.
sCD105 levels are increased in patients with severe FH and
decrease after extracorporeal elimination what is the first observation.
Supported by the research task IGA MH CZ NR/8505/3.
1211
A NEW VARIANT MLL-SEPT2 FUSION TRANSCRIPT IN THERAPY-RELATED ACUTE
MYELOID LEUKEMIA WITH T(2;11)(Q37;Q23)
A. Buijs, 1 E. van Binsbergen, 1 O. de Weerdt2 1 University Medical Center Utrecht, UTRECHT, Netherlands; 2 St. Antonius
Hospital, NIEUWEGEIN, Netherlands
Background. 11q23 MLL gene rearrangements are found in acute
leukemias and are associated with a poor prognosis. To date, 87 different
chromosome bands have been described with 11q23 MLL rearrangements
and about 51 fusion genes have been identified. 5-10% of MLL
gene rearrangements are found in patients with therapy-related leukemia
after treatment with topoisomerase II inhibitors, or high-dose radiotherapy.
T(2;11)(q37;q23) is a rare recurrent abnormality in (therapy-related)
acute myeloid leukemia (t-AML). Methods and Results. A 66-year-old male
was diagnosed with t-AML (FAB AML-M2) after previous chemotherapy
for gastric carcinoma. Cytogenetics showed a 46,XY,t(2;11)(q37;
q23)[4]/51,sl,+8,+17,+21,+22,+mar[10]/46,XY[5] karyotype. FISH analysis
demonstrated an 11q23 MLL rearrangement. In the process to identify
the MLL-partner gene on chromosome 2 band q37 a paper was published
describing the characterization of a MLL-SEPT2 fusion transcript
in a t(2;11)(q37;q23)-positive t-AML (FAB AML-M4). To investigate the
presence of a MLL-SEPT2 fusion mRNA in our case, RT-PCR and
sequencing analysis was performed, revealing an in-frame MLL-
SEPT2?fusion of exon 6 of MLL to exon 3 of SEPT2. Therefore, the MLL
moiety lacks exon 7 that is included in the previously reported fusion
transcript. Conclusions. We report on a novel t(2;11)(q37;q23) positive t-
AML resulting in a new variant MLL-SEPT2 fusion transcript (type II).
A review of the literature demonstrated that t(2;11)(q37;q23) is a rare
recurrent chromosomal aberration thus far reported in two cases of de
novo AML, and two cases of t-AML, not linked to any specific AML FABsubtype.
It has been founded as a sole abnormality or in addition to other
aberrancies. In our case the t(2;11)(q37;q23) was found as a sole aberration
with clonal evolution towards additional numerical and structural
changes.
1212
DIVERSE ANTIOXIDANT EFFECTS ON PRENEOPLASIC LESIONS INDUCTION
IN PROMOTION STAGE IN A CHEMICAL HEPATOCARCINOGENESIS MODEL
R. García-Román, 1 D. Salazar-González, 2 S. Fattel-Fazenda, 1 J. Arellanes-Robledo,
1 O. Beltrán-Ramírez, 1 S. Villa-Treviño1 1 2 CINVESTAV, MÉXICO, D.F., Mexico; Instituto Tecnológico de Tijuana,
TIJUANA, B.C., Mexico
Background. The Transcriptional factor NF-κB is involved in oncogenesis
process due to cellular proliferation regulatory proteins. NF-κB is a
transcriptional element activated by several stimuli, including oxidative
stress. After several inductors, NF-κB inhibitors IκB’s are rapidly phosphorylated
by IKK kinase and ubiquitinated by E3 ubiquitin-ligase to
subsequent degradation by 26S proteasome. Then, NF-κB free translocates
to nucleus. Current evidence involves oxidative stress to inflammation
and degenerative diseases, such as rheumatoid arthritis, Alzheimer
and carcinogenesis. One of major approach to inhibit or diminish the
redox transcription factors activation has been the antioxidant therapy.
The antioxidants S-Adenosyl-methionine (SAM), N-acetyl-cysteine and
Quercetin, have been able to protect in degenerative disorders. Aims. To
determine the role of antioxidants in preneoplasic lesions induction and
the modulation of NF-κB signaling pathway. Methods. Fisher rats 344
were subjected to carcinogenic treatment. Rats were initiated with
Diethyl-nitrosamine (DEN) (200 mg/kg i.p.). At 7 day after initiation, 2-
Acetyl-amino-fluorene (2-AAF) was administered by gavage during 3
days (25 mg/kg). On day 10, rats were subjected to Partial Hepatectomy
(PH). The antioxidants were administered separately during the carcinogenic
treatment (TC), since 24 hr after DEN until 2 hr before PH. In order
to evaluate the antioxidant effects, the caffeic acid phenethyl ester, a
selective NF-κB inhibitor was administered 2 hr before PH. All groups
were sacrificed 30 min after PH. The preneoplasic lesions induction was
determined by tumor markers Gamma-glutamyl-transpeptidase (GGT)
and Glutathione-S-transferase placental (GST-p). The nuclear levels of
NF-κB and the signaling pathway activation were determined by west-
12 th Congress of the European Hematology Association
ern blot analysis. The glutathione levels were measured by Ellman’s
method. Results. The carcinogenic treatment induced preneoplasic
lesions, Rel A/p65 nuclear levels increase, IKKα/IKKβ‚ and IκB-α phosphorylation.
The SAM treatment diminished 64% the GGT preneoplasic
foci and 68% in GGT+ area. However, GST-p tumor marker was not
diminished. SAM exerted an antioxidant effect incremented 104.7% glutathione
levels above normal liver. Also, SAM caused a significant reduction
of 86.8% in Rel A/p65 nuclear levels in comparison to TC, a 47.3%
IKKα/IKKβ and 54.6% IkB-α phosphorylation decrease. NAC caused a
significant GGT foci number decrease (69.1%), and area (63.95%). The
GST-p number foci and area were significant diminished in 57% and 73.
9%, respectively. However, glutathione levels were not altered. Unexpectedly,
NAC did not diminish the Rel A/p65 nuclear levels, although
reduced 54% IKK·/IKK‚ and 65.1% IκB-α phosphorylation. Quercetin
flavonoid only diminished 83.2% the GGT+ area, although reduced the
GST-p number foci and area, 45.8% and 86.4% respectively. Quercetin
not exerted an antioxidant effect in glutathione levels, while Rel A/p65
nuclear levels were considerably reduced. IKKα/IKKβ and IkB-α phosphorylation
diminution were not observed.
Figure 1. Diminution of preneoplasic lesion by antioxidant treatment. A. Histological
determination of GGT activity in TC and antioxidant treatments. B.
Quantification of preneoplasic nodules and area. Aroows indicate the GGT
cellular localization.
Conclusions. The NF-κB pathway is a key component of the redox signaling
in cancer process. The reactive oxygen species are involved in
preneoplasic lesion induction on liver cancer. The glutathione precursors
SAM and NAC exerted a NF-κB diminution by IKK and IkB-α phosphorylation
inhibition. The preneoplasic lesion diminution of quercetin is an
independent mechanism of NF-κB.
1213
INCIDENCE OF FLT-3 MUTATIONS IN IRANIAN ADULT PATIENTS WITH DIFFERENT
SUBTYPES OF ACUTE MYELOID LEUKAEMIA
F. Zaker, M. Mohammadi, A. Kazemi
Iran University of Medical Sciences, TEHRAN, Iran
Background. Fms-like tyrosine kinase 3 (FLT3) is a member of the class
III receptor tyrosine kinase family along with KIT and FMS. Two clusters
of activating FLT3 mutations are known: FLT3-internal tandem
duplications (FLT3-ITD) in the juxtamembrane (JM) domain in 20-25%
and FLT3-point mutations within the activation loop of the tyrosin
kinase domain (TKD), which mostly affects asparate 835 (D835) in 7-
10% of patients respectively.These abnormalities considered as the most
frequent molecular abnormalities in AML, which predict unfavorable
outcome. However, the data concerning the incidence and associations
with patients characteristics vary in different studies. Aims. The aim of
study was to analyze the impact of FLT3 mutations in cohort of 202
newly diagnosed Iranian patients with differents subtypes of AML and
to correlate FLT3 positive status with some clinical and biological features.
Methods. All adult patients diagnosed in main haematology centers.
Peripheral blood or bone marrow from 202 patients were screened.
Genomic DNA polymerase chain reaction (PCR) assay was performed
to detect FLT3-ITDs located from exon 11 to exon 12 and interon 11
(PCR band(s)>329bp). Asp 835 point mutations in exon 20 of the FLT3
haematologica/the hematology journal | 2007; 92(s1) | 443