MDR-1 and GST Polymorphisms Are Involved in Myelodysplasia Progression,

Abstract 3507

Drug-metabolizing enzymes are responsible for the metabolism of several chemotherapeutic agents and may be involved in resistance to chemotherapy. A better knowledge of drug metabolism may improve the selection of treatments and the survival in hematopoietic malignancies, especially in acute leukemia, including acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL), and also myelodysplastic syndromes (MDS), which are clonal hematopoietic malignancies with poor survival. Polymorphisms in many enzymes can influence their enzymatic activity and modify treatment response and resistance.

Drug metabolism is divided in two phases. CYP2B6 gene is involved in phase I and is responsible for drug activation. Polymorphism CYP2B6 G15631T leads to Gln172His. Glutathione S-transferases (GST) and NQO1 genes are involved in phase II of metabolism and are responsible for conjugation and detoxification of xenobiotics. GSTT1 and GSTM1 genes have a polymorphic homozygous deletion. NQO1 C609T polymorphism results in Pro187Ser, which produces low enzyme activity. Another gene involved in the treatment resistance process is MDR-1 that encodes P-glycoprotein (Pgp) which is responsible for drug efflux. MDR1 C3435T is a silent polymorphism, but leads to decreased protein expression.

All of these polymorphisms have been related to leukemia risk. However, the association of these polymorphisms with clinical outcomes in leukemia remains unclear, and to our knowledge no study has accessed these polymorphisms in MDS progression yet. Therefore, we evaluated the influence of CYP2B6 G15631T, GSTT, GSTM1, NQO1 C609T and MDR-1 C3435T in MDS progression and in acute leukemia remission and relapse.

Genomic DNA was extracted from 66 MDS (WHO classification: RCUD=9, RARS=1, RCMD=25, RCMD/RS=11, RAEB I=10, RAEB II=7 and del5q=3) and 92 acute leukemia patients (AML=67 and ALL=25), median age 56 (18–91). MDS progression was defined by change of IPSS or WHO classification to a higher risk category, which occurred in 27% (18/66) of MDS patients. Remission was achieved in 43.2% (29/67) and 54.3% (50/92) and relapse occurred in 15.7% (6/38) and 16.9% (10/59) in AML and acute leukemia patients, respectively. The polymorphisms were investigated by PCR-RFLP or PCR-Multiplex.

The frequency of GST deletions and MDR-1 CC genotype was lower in non progression patients compared to patients with progression; GST: 21% vs. 50% (p=0.03, OR=0.263 95% 0.083 to 0.837); MDR-1 gene: 19% vs. 55% (p=0.005, OR=5,417 95% 1.666 to 17.61). No significant differences were found among other polymorphisms and progression rate or IPSS score.

In acute leukemia, patients that achieved remission had a lower frequency of NQO1 C609T polymorphism CT+TT genotype, compared to patients that did not achieve remission: 26.3% vs. 51.7% in AML (p=0.033, OR=0.333 95% 0.1195–0.9298), and 25.4% vs. 51.5% in acute leukemia (p=0.025, OR=0.3622 95% 0.1473–0.8908). No significant differences were found among other polymorphisms, remission or relapse rate.

Our results indicate that MDR-1 C3435T CT+TT genotypes may have a protective effect against MDS progression. MDR-1 mutated allele leads to low Pgp activity, therefore our results are in accordance with the literature which has previously reported a high expression of MDR-1 in high risk MDS and AML. We also showed that GST deletion was associated with increased risk of MDS progression. The GST deletions have been related with worse clinical outcome in several types of cancer including AML but, as far as we know, this is the first description in MDS progression. In AML patients, we confirmed that NQO1 C609T influences the remission rate of acute leukemia, especially in AML patients, corroborating previous data showing the association of the CT+TT genotypes with worse clinical outcomes in AML and ALL patients.