sem informação1001PB173168568520th Congress of European-Hematology-Associatio

Albuquerque, D.

Fachel, A.

Ferreira, R.

Pagnano, K.

Ribeiro, B.

Silveira, R.

Souza, C.

Vergilio, B.

Verjovski-Almeida, S.

Haematologica

English

Repositorio da Producao Cientifica e Intelectual da Unicamp

UNIVERSIDADE ESTADUAL DE CAMPINAS
SISTEMA DE BIBLIOTECAS DA UNICAMP
REPOSITÓRIO DA PRODUÇÃO CIENTIFICA E INTELECTUAL DA UNICAMP
Versão do arquivo anexado / Version of attached file:
Versão do Editor / Published Version
Mais informações no site da editora / Further information on publisher's website:
https://haematologica.org/issue/view/284
DOI: 10.3324/%25x
Direitos autorais / Publisher's copyright statement:
© by Fondazione Ferrata Storti. All rights reserved.
DIRETORIA DE TRATAMENTO DA INFORMAÇÃO
Cidade Universitária Zeferino Vaz Barão Geraldo
CEP 13083-970 – Campinas SP
Fone: (19) 3521-6493
http://www.repositorio.unicamp.br
namely, the frequency of UGT1A1(TA)7 repeat polymorphism is high in Cau-
casians, whereas it is low in Asians (Beutler et al. Proc. Natl. Acad. Sci. USA
95 (1998) 95, 8170–8174).
Aims: The aim of this study was to investigate the association between
UGT1A1 gene promoter polymorphism and hyperbilirubinemia in Korean CML
patients treated with NIL and RAD as a frontline therapy.
Methods: A total of 94 newly diagnosed chronic phase CML patients who treated
with frontline NIL (n=42) and RAD (n=52) was screened for UGT1A1 promoter
polymorphism genotype analysis. We used the High Pure PCR Template Prepa-
ration Kit (Roche, Germany) to prepare genomic DNA from whole blood and geno-
typed by direct sequencing of the 253- to 255-bp fragments produced by PCR. 
Results: The (TA)6/(TA)6 homozygote and (TA)6/(TA)7 heterozygote were seen
in all genotyped population and frequency of (TA)6/(TA)6 homozygote was
77.7% (73/94) in our patients. (TA)6 /(TA)6 homozygote predominated with
78.9% of the alleles in the RAD group and 76.2% in the NIL group. Relative
risk for each genotype presented in Table 1, with hyperbilirubinemia defined as
CTCAE grade 2 or greater observed at any post-baseline point. The relative
risks for 6/6 genotype versus 6/7 genotype was 3.9 with 95% CIs of (0.7, 20.3)
in the RAD group compared with 10.5 (2.0, 54.3) in the NIL group and NIL
group showed significantly high association with UGT1A1 gene promoter poly-
morphism (P<0.05).
Table 1. Relative risk calculations prevalcence of hyperbilirubinemia.
Summary and Conclusions: This finding suggests that UGT1A1 gene pro-
moter polymorphism may be an important determinant of hyperbilirubinemia in
CML patients with NIL therapy, but not in RAD. However other mechanisms
should be explored in patients who have significant hyperbilirubinemia with
RAD therapy. Updated data with longer follow-up duration will be presented in
the meeting
PB1730
IMPACT OF MULTIDRUG RESISTANCE GENE 1 (MDR1) C3435T
POLYMORPHISM ON CHRONIC MYELOID LEUKEMIA RESPONSE TO
TYROSINE KINASE INHIBITORS
Y. Elnahass1,* M. mattar2, H. El Leithy2
1Clinical Pathology, National Cancer Institute, 2Cinical hematology, School of
Medicine, Cairo, Egypt
Background: Single nucleotide polymorphisms (SNPs) of multiple drug resist-
ance (MDR1) gene are associated with altered P-glycoprotein (p-gp) activity
and contribute to resistance to tyrosine kinase inhibitors (TKIs) in chronic
myeloid leukemia (CML).
Aims: We aimed to demonstrate the association between MDR1 gene C3435T
polymorphism and molecular response in newly diagnosed chronic phase (CP)
CML patients to standard dose upfront imatinib and nilotinib therapy.
Methods: MDR1 C3435T was genotyped using polymerase chain reaction
Restriction Fragment Length Polymorphisms (PCR-RFLP) at diagnosis. BCR-
ABL1 transcripts level was measured by Real Time Quantitative polymerase
chain reaction (RQ-PCR) at diagnosis then every 3 months. 
Results: This study included 74 Philadelphia (Ph’) positive CP-CML patients;
38 males and 36 females. Median age at diagnosis was 38 years (18-78). Medi-
an BCR-ABL1 level was 101%. Forty patients received imatinib (54%) while 34
received nilotinib (46%). Optimal response at 12 month was 35% in the imatinib
arm versus 80% in the nilotinib arm (P=0.001). The frequency of MDR1 SNP
C3435T was 46%, 32% and 22% for CC, TT and CT genotypes, respectively.
Optimal response at month 12 differed significantly between imatinib and nilo-
tinib among patients with MDR1 C3435TT genotype (11% versus 83%, respec-
tively, P=0.002) while less significant difference was found between the two
drugs in CC and CT genotypes (35% vs. 75% and 60% vs. 83%, respectively,
P=0.042 & P=0.588).
Summary and Conclusions: MDR1 C3435TT may be used as an additional
criterion for initiating nilotinib instead of imatinib as front line therapy for CP-
CML patients. We demonstrated the usefulness of MDR1 SNP polymorphism
in the identification of CML patients who may or may not respond optimally to
imatinib.
PB1731
DIFFERENTIAL EXPRESSION OF ABCF2 IN NEWLY DIAGNOSED AND
DASATINIB-TREATED CHRONIC MYELOID LEUKEMIA PATIENTS
B. Ribeiro1,* R. Ferreira1, R. Silveira1, Â. Fachel2, S. Verjovski-Almeida2,
B. Vergílio1, D. Albuquerque1, C. Souza1, K. Pagnano1
1Hematology and Hemotherapy Center, University of Campinas-UNICAMP,
Campinas, 2Departamento de Bioquímica, Instituto de Química, Universidade
de São Paulo, São Paulo, Brazil
Background: ABCF2 was previously identified by our group as genes differ-
entially expressed in CML patients which are resistant to imatinib, in samples
collected before and after dasatinib treatment (responsive and resistant) in a
microarrays analysis study (SILVEIRA, RA et al. Hematology;19(1):31-41,2014).
ABCF2 gene is a member of the ATP binding cassette (ABC) transporter family
and although its function is not clear, studies with colorectal and breast cancer
showed an association of low expression of ABCF2 and poor prognosis and
non-response to palliative chemotherapy. The role of ABCF2 in CML patho-
genesis is unknown. 
Aims: The aim of this study was to analyse the expression profile of ABCF2 in
CML patients without previous treatment, in CML patients treated with dasatinib
(after imatinib failure) and in healthy donors.
Methods: Total RNA extraction of mononuclear cells from peripheral blood,
transcription to cDNA, and qPCR were performed to analyze differential gene
expression. ACTB and GAPDH were used as endogenous control. geNorm
program was used to estimate the gene expression in arbitrary units (A.U.).
Results were expressed as median and compared using non-parametric tests
(Mann Whitney or Kruskal-Wallis). We evaluated 13 healthy donors (control
group) and 39 CML patients treated with dasatinib in second line after imatinib
failure: 25 responsive to dasatinib, all with complete cytogenetic response
(CCyR), 15 of them with major molecular response (MMR) and 14 patients
resistant to dasatinib. We also analyzed 9 samples collected at CML diagnosis
from the group that was responsive to dasatinib. Only one patient of this group
had no sample available after dasatinib treatment. 
Results: ABCF2 expression was down-regulated in the newly diagnosed CML
samples and in patients treated with dasatinib compared to control group (0.15
[0.05 – 0.91] versus (vs.) 0.35 [0.04 – 3.07] versus (vs.) 2.5 [0.61 – 4.84] P<
0.0001). There was no difference of expression between patients at diagnosis
and patients treated with dasatinib (all patients) (P=0.09). However, ABCF2
expression was significantly lower in CML dasatinib-resistant patients when
compared to dasatinib-responsive patients with MMR (0.35 [0.05 – 2.21] versus
(vs.) 1.19 [0.14 – 3.07] P=0.02). The expression of ABCF2 was down-regulated
in 8 CML patients at diagnosis and its expression increased after treatment
with dasatinib in patients that achieved MMR (0.22 [0.06 – 0.91] versus (vs.)
1.20 (0.14 – 2.73] P=0.049).
Figure 1.
Summary and Conclusions: ABCF2 is down-regulated in newly diagnosed
CML when compared to the healthy donors and to dasatinib treated patients.
On the other hand, up-regulation of ABCF2 was observed after treatment in
patients which achieved MMR with dasatinib. ABCF2 might be involved in
mechanisms associated with the development of CML or resistance. Further
studies are necessary to clarify the role of ABCF2 in CML. 
PB1732
DIDO 2 LOW EXPRESSION IN CML IS LINKED TO APOPTOSIS
RESISTANCE
M. Coelho1,* A.P. Marsola1, S. Burin1, M. Rocha-Junior1, A. Ferreira1,
S. Haddad1, B. Simões2, R. Panepucci3, C. Martinez4, F. Castro1
1Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, 2Faculdade
de Medicina de Ribeirão Preto-USP, 3Fundação Hemocentro de Ribeirão Preto,
Ribeirão Preto, Brazil, 4Centro Nacional de Biotecnologia-CSIC, Madrid, Spain
Background: Chronic myeloid leukemia (CML) is a myeloproliferative neo-
haematologica | 2015; 100(s1) | 685
Vienna, Austria, June 11 – 14, 2015


Differential expression of ABCF2 in newly diagnosed and dasatinib-treated chronic myeloid leukemia patients

http://repositorio.unicamp.br/jspui/bitstream/REPOSIP/354962/2/000361204904273.pdf

Differential expression of ABCF2 in newly diagnosed and dasatinib-treated chronic myeloid leukemia patients

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