THE BIOLOGICAL SIGNIFICANCE OF THE MULTIDRUG-RESISTANCE GENE MRP IN INVERSION-16 LEUKEMIAS

Multidrug resistance represents an important mechanism by which leukae mic and solid tumour cells escape cell death after exposure to anthrac yclines and other natural products. Acute myeloid leukaemia (AML) asso ciated with the inversion chromosome 16: inv(16)(p13q22) has a favoura ble prognosis and is known to be chemosensitive. The inversion chromos ome is seen in a number of FAB subclasses but is most commonly associa ted with acute myelomonocytic leukaemia with abnormal eosinophils, M4E o. It results in the creation of a fusion between the myosin heavy cha in gene (MYH11) on the short arm and the gene for a transcription fact or, core binding factor beta (CBFB) on the long arm. In a subset of th ese inv(16) AML patients, inversion also results in loss of the gene f or the multidrug resistance protein (MRP) at the short arm breakpoint. This gene maps to 16p13.13, centromeric to the primary short arm brea kpoint, separated from MYH11 by a distance of approximately 150kb. Del etion of the MRP gene has been demonstrated by in situ hybridisation, gene dosage studies and by loss of heterozygosity of a flanking micros atellite marker (D16S405), Twenty two patients with inv(16) leukaemia were analysed for deletion of the MRP gene. Deletion of the gene was d etected in seven patients, fourteen patients showed retention of the g ene and in one case the findings were indeterminate, Clinical data fro m 13 of these patients were analysed revealing deletion of the MRP gen e to be significantly associated with longer time from diagnosis until failure (death or relapse from complete remission) in these patients (p = 0.007). From this work and the growing literature concerning MRP, it appears likely that the deletion of an MRP allele, may favourably affect the biology of inv(16) AML and may have important prognostic im plications.