Deletion of the multidrug resistance protein 1 (MRP1) gene in acute myeloid leukemia patients with inversion 16: expression of MRP1 homologues

TO THE EDITOR

In the prospective study of Döhner et al,1 it is described that the deletion of the multidrug resistance protein (MRP1) gene has no prognostic impact in acute myeloid leukemia (AML) patients with an inversion on chromosome 16. These findings are in agreement with the results we recently described,2 and might be due to the fact that the expression of MRP1 homologues can be upregulated in the case of MRP1 deletion.

MRP1, encoded by the MRP1 gene located on chromosome 16p13, is a member of the superfamily of ATP-binding cassette (ABC) transporters. MRP1 has been shown to transport a broad range of organic substrates, and the expression of MRP1 results in resistance to different classes of chemotherapeutic agents. The MRP family of proteins consists of at least six family members, MRP1 to MRP6.3 However, the role of the MRP1 isoforms is not yet well defined. MRP2, MRP3 and MRP5 have been described to transport chemotherapeutic agents, such as cisplatin, doxorubicin, etoposide and 6-mercaptopurine, but less is known about the transport mechanisms of the proteins MRP4 and MRP6. Another membrane transporter, P-glycoprotein (P-gp) encoded by the MDR1 gene, has also been shown to transport chemotherapeutic drugs. The simultaneous expression and function of both proteins has been shown to be correlated with poor overall survival in AML.4

A subgroup of patients with AML, most commonly patients with the French–American–British (FAB) classification M4Eo, show the chromosomal inversion 16 inv(16)(p13q22), resulting in a fusion of the MYH11 gene on 16p13 with the CBFB gene on 16q22. Deletion of 1 MRP1 allele has been demonstrated in a subgroup of AML patients with inv(16) and patients with the deletion showed an increased duration of disease-free survival as compared with patients without deletion.5 However, these findings could not be confirmed in several other studies. In addition the study of Döhner et al1 in 25 AML patients with inv(16) also showed no correlation between MRP1 deletion and remission duration.

In our study2 we determined MRP activity with a flow cytometric assay6 in the context of MRP1 deletion in 11 inv(16) AML patients. A correlation was observed between MRP activity and the occurrence of MRP1 deletions (r = 0.91, P < 0.01), suggesting an important role for MRP1. However, we observed an up-regulation of the MRP1 homologues MRP2 and MRP6, especially in those patient samples with one MRP1 deletion. In addition we observed a high activity of P-gp in one of the AML patients with MRP1 deletion. No association was found between MRP1 deletion and clinical outcome in the AML patients. In conclusion, it seems likely that in the case of a deletion of a transporter gene, the function might be compensated for by other transporter proteins, which might also affect the clinical outcome in inv(16) AML patients.