High levels of lung resistance related protein mRNA in leukaemic cells from patients with acute myelogenous leukaemia are associated with inferior response to chemotherapy and prior treatment with mitoxantrone

Abstract

Summary. Expression of the mdr1 (multidrug resistance), mrp (multidrug resistance associated protein), and lrp (lung resistance related protein) genes is associated with transport related MDR (multidrug resistance). We quanti®ed mRNA levels of these genes using competitive reverse transcription polymerase chain reaction (RT-PCR) in 128 samples of leukaemic cells from 92 patients with acute myelogenous leukaemia (AML).There was a wide variation between the samples in mRNA levels of all three genes. The mean mdr1 mRNA level was 1´3 transcripts per cell (range undetectable to 15´8), the mean mrp level was 7´9 (range 0´1±36´2) and mean lrp 3´9 (range 0´1±29).Lrp mRNA levels were higher in samples drawn at diagnosis from the 15 patients with resistant disease than from the 37 with chemosensitive disease (4´9 SD 3´1 v 2´9 SD 2´3, P 0´016). Neither mdr1 nor mrp mRNA levels were predictive for response to chemotherapy. In samples from patients who had received chemotherapy, those that had received mitoxantrone (n 24) had higher lrp mRNA levels (mean 4´8, SD 2´5) than those that had not (n 20, mean 2´8, SD 2´4, P 0´012).In conclusion, the results indicate that lrp expression is associated with inferior response to chemotherapy in AML and that lrp expression increases after exposure to mitoxantrone.

Prognostic Significance of Multidrug Resistance Gene 1 (MDR1), Multidrug Resistance-related Protein (MRP) and Lung Resistance Protein (LRP) mRNA Expression in Acute Leukemia

“…Therefore, LRP mRNA expression was particularly influential in outcomes following induction chemotherapy in AML patients. This correlation between LRP expression and treatment outcome is consistent with suggestions that chemosensitive leukemic cells have low LRP mRNA levels in AML (10, 13). …”

Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML)

“…Previous studies have shown conflicting results with regards to MDR1, MRP and LRP/MVP upregulation at relapse, probably because they were often performed in a heterogeneous pool of diagnostic, relapse and secondary AML samples (Table 5). 12,16,29,[52][53][54][55][56][57][58] It has often been suggested that MDR1 expression at the time of relapse is higher as compared to diagnosis. 33,[59][60][61][62][63][64][65] In the present study, we did not find a higher level of MDR1 mRNA, nor P-glycoprotein function and expression at relapse or in refractory disease in these AML patients.…”

Cellular Functions of Vaults and their Involvement in Multidrug Resistance

“…A leukemia type repeatedly reported to express MVP in a substantial proportion of patients at diagnosis is acute myeloid leukemia (AML) [81][82][83][84][85][86][87][88][89][90][91][92]. One problem with the data regarding MVP expression in AML is the profound variation in the percentage of MVP-positive AML cases reported, varying between 34% [81] and 69% [93] when using immunocytochemistry but reaching values of up to 91% by RT-PCR [94] and down to 26% by flow cytometry [95].…”

“…One problem with the data regarding MVP expression in AML is the profound variation in the percentage of MVP-positive AML cases reported, varying between 34% [81] and 69% [93] when using immunocytochemistry but reaching values of up to 91% by RT-PCR [94] and down to 26% by flow cytometry [95]. Several studies found an association between MVP expression and therapy resistance [81][82][83][84] as well as in some cases also patient prognosis [90][91][92], whereas others found no association with either parameter [85][86][87][88][89]. In vitro MVP expression did neither correlate with daunomycin accumulation nor cytotoxicity of patient-derived AML cells [96].…”