Overexpression of lung‐resistance protein and increased P‐glycoprotein function in acute myeloid leukaemia cells predict a poor response to chemotherapy and reduced patient survival

Abstract

Summary.We investigated the role of the drug resistancerelated proteins LRP, MRP and Pgp and the apoptotic suppressor, bcl-2, in relation to other clinical characteristics, with respect to response and survival in 91 patients with newly diagnosed AML, treated with standard chemotherapy. Multivariate analysis showed that poor response to chemotherapy was associated with increasing age (P ¼ 0·0004), LRP expression (P ¼ 0·0001) and Pgp function (P ¼ 0·015). The significant predictors of both leukaemia-free survival (LFS) and overall survival (OS) were LRP (LFS, P ¼ 0·01; OS, P ¼ 0·0001), Pgp function (LFS, P ¼ 0·0001; OS, P ¼ 0·0003) and cytogenetic abnormalities (LFS, P ¼ 0·0001; OS, P ¼ 0·0005). Patients with the lowest expression of LRP and Pgp function and favourable karyotype (group I) had an LFS of 30·2 months compared to 8·5 months in the group with the highest expression of LRP and Pgp and poor prognosis karyotype (group III, P ¼ 0·002). OS decreased from 75·4 months in group I to 7·9 months in group III patients (P < 0·0001). Neither MRP nor bcl-2 were significantly associated with chemotherapy response and survival. Correlations were found between increasing expression of LRP and older age (P ¼ 0·05) and an unfavourable karyotype (P ¼ 0·005), but these variables were independent of each other in analysis of treatment response and patient survival. Our findings suggest that both LRP and Pgp are clinically relevant drug-resistance proteins and it may be necessary to modulate both LRP and Pgp functions in order to reverse the multidrug resistance phenotype in AML.

Drug resistance factors in acute myeloid leukemia: a comparative analysis

“…The present univariate results on LRP confirm our initial results in 82 patients, 12 and are consistent with published studies. 11,20,26 List et al 11 reported a significant association between LRP overexpression and both an inferior response to induction chemotherapy and a trend toward shorter survival on, in comparison to our study, a more heterogeneous study Complete remission rates and median overall survival dependent on the number of risk factors (age у60 years, poor karyotype, LRP expression) are shown.…”

“…9,10,20 In a recent study by Marie's group, outcome of induction chemotherapy correlated with MRP function but not with MRP expression. 28 Shorter survival in the presence of bcl-2 expression (Figure 1) has recently also been shown by others.…”

“…Data from multivariate analyses on LRP are currently available also from two other groups. 11,20 List et al 11 found that LRP but not P-gp had independent predictive significance with regard to response to induction chemotherapy. Borg et al 20 performed a multivariate analysis that included age, white blood cell count, CD34, bcl-2, LRP, MRP, P-gp expression as well as rhodamine 123 efflux, FAB subtype, and cytogenetic subgroups.…”

“…In the study by Hart et al 26 LRP expression predicted response of induction chemotherapy. Borg et al 20 demonstrated that LRP is an unfavorable predictive and prognostic factor in patients with de novo or secondary AML. However, our findings are in contrast to other studies including the one of the Southwest Oncology Group in younger AML patients.…”

Flow cytometry‐based assessment of mitoxantrone efflux from leukemic blasts varies with response to induction chemotherapy in acute myeloid leukemia

“…There are 49 human genes in the ATP-binding cassette (ABC) transporter superfamily encoding transmembrane proteins, which mediate drug efflux via ATP-dependent pumps (17)(18)(19)(20)(21). Among the ABC transporters, expression of multidrug resistance protein 1 (MDR1 or P-glycoprotein) and breast cancer resistance protein 1 (BCRP1) have been associated with chemotherapy resistance in AML in some studies (22)(23)(24)(25)(26)(27)(28) although not in all (29)(30)(31)(32). One possible reason for the conflicting prognostic relevance suggested for ABC transporter expression in AML is the variety of methods used to assess that expression in previous studies (33).…”