Q141K Polymorphism of ABCG2 Protein Is Associated with Poor Prognosis In Adult Acute Myeloid Leukemia Treated with a Idarubicin-Based Chemotherapy Protocol

Abstract 4941

Since the multidrug resistance phenotype was first observed 30 years ago, other 48 proteins, belonging to an evolutionary highly conserved family of transport proteins, named ABC proteins, has been identified and grouped in eight subclasses, according to divergent evolution. In eukaryotes, ABC proteins are involved in transport across the membrane to extracellular space or into intracellular organelles playing an important role in cell physiology. Almost three distinct subfamilies (B, C and G) have been recognized to transport a wide variety of amphipatic or hydrophobic molecules, including most of anticancer drugs compounds, affecting drug absorption, disposition, metabolism, excretion and toxicity (ADMEtox) and has been associated to chemotherapy failure in solid and hematologic neoplasia. In particular the role of ABCG2 has been pinpointed over the past years for its high expression on primitive hematopoietic and on progenitors cells and for its ability to confer to the cancer cell the properties of cancer stem cell, with increased survival capacity. At present over 40 single nucleotide polymorphisms of ABCG2 protein have been identified. Among them the 421C>A (Q141K) variant has been shown able to alter protein function and to modify in vitro sensitivity to many anticancer drugs, compared to the wild type protein. In the present paper we have evaluated the incidence and the impact on therapy outcome in a series of 100 caucasic patients with acute myeloid leukemia, receiving the same chemotherapy program including idarubicin. Q141K polymorphism was detected in 19/100 (19%) patients, without correlation with any clinical-biological characteristic at diagnosis (such as sex, age, peripheral blast count, FAB subtype, karyotytpe, CD34 expression). ABCG2 protein was overexpressed in 10/19 (52.6%) of mutated patients and in 37/83 (44.5%) of patients expressing the wt form of ABCG2 and no difference in intensity of ABCG2 expression was observed in the two groups. Again no difference in ABCG2 mRNA transcription was detected between patients carrying wt or polymorphic protein. Complete remission rate was comparable in wt and mutated patients (38/81, 45,7% vs 10/19, 52,6%). However patients with Q141K polymorphism (irrespective to the intensity of expression of ABCG2) protein) had a leukemia free survival comparable to patients overxpressing wt protein, and significantly shorter than patients without wt ABCG2 overepxression (chi square 12,2, p=0,002, logrank test). In conclusion our data demonstrated Q141K polymorphism of ABCG2 transporter protein identified a subset of patients with high probability of relapse when treated with idarubicin suggesting that other drugs should be considered in consolidation/maintenance treatment to improve patients outcome. Finally the impact of Q141K polymorphism on treatment toxicity is under investigation.

Work supported by PRIN 2007WEYB34-004