Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype [see comments]

Abstract

The multidrug-resistance gene, MDR1 is expressed in many normal tissues, but little is known about its expression in normal hematopoietic cells. Using the monoclonal antibody C219 and flow cytometric analysis, P-glycoprotein (P-gp) was found to be expressed in all peripheral blood (PB) subpopulations (CD4, CD8, CD14, CD19, CD56) except granulocytes. To specifically determine MDR1 gene expression, these PB subpopulations were isolated by fluorescence-activated cell sorting (FACS) and analyzed for MDR1 mRNA by polymerase chain reaction (PCR). All subsets were positive by PCR, but only minimal MDR1 mRNA was detected in monocytes and granulocytes. Significant efflux of Rhodamine- 123 (Rh-123), a measure of P-gp function, was detected in CD4+, CD8+, CD14+, CD19+, and CD56+ cells but not in granulocytes. Next, PCR- analysis was performed on FACS-sorted bone marrow (BM) cells to assess MDR1 expression in different maturational stages. Precursors (CD34+), early and late myeloid cells (CD33+/CD34+, CD33+/CD34-) as well as lymphocytes of the B-cell lineage (CD19+/CD10+, CD19+/CD10-) expressed the MDR1 gene. BM monocytic cells (CD33++/CD34-) were negative, and a very weak signal was detected in erythroid cells (glycophorin A+). Significant Rh-123 efflux was found in CD34+, CD10+, CD33+, and CD33++ BM cells, but not in glycophorin A+ cells. We conclude that PB and BM lymphocytes, PB monocytes, BM progenitors, and immature myeloid cells, but not late BM monocytes, erythroid cells, and PB granulocytes, express MDR1 mRNA and a functional P-gp. These results have to be taken into account when MDR1 expression is determined in tumor samples containing normal blood cells.

ABCB1 Variation Affects Myelosuppression, Progression‐free Survival and Overall Survival in Paclitaxel/Carboplatin‐treated Ovarian Cancer Patients

“… describe higher ABCB1 expression for 3435T allele carriers in hepatocellular carcinoma samples. Furthermore, cell populations in peripheral blood and bone marrow express ABCB1 . The idea is that lowered expression of ABCB1 leads to decreased cellular clearance of paclitaxel, higher intracellular concentrations and thus more cell death and greater toxicity.…”

Expression of mdr1 and mrp in the normal B‐cell homologue of B‐cell chronic lymphocytic leukaemia

“…This study confirmed low level expression of Pgp in B cells with significant verapamil-blocked efflux of R123. In bone marrow cells Drach et al (1992) demonstrated that mdr1 mRNA was more readily detected in CD19 + /CD10 ¹ than CD19 + /CD10 + cells.…”

“…They were unable to detect Pgp expression due to non-specific binding of antibodies to B cells in the second stage of Pgp labelling. Drach et al (1992) examined sorted peripheral blood and bone marrow lymphocytes for Pgp expression. This study confirmed low level expression of Pgp in B cells with significant verapamil-blocked efflux of R123.…”

Multidrug transporter activity in lymphocytes

“…However, studies of transporters expressed by lymphocytes conflict. In humans, for example, it has been suggested that P‐gp is expressed by anywhere between 20 and 80% of B cells, and between 30 and 100% of CD4 + T cells ( Chaudhary et al ., 1992 ; Drach et al ., 1992 ; Klimecki et al ., 1994 ; Pilarski et al ., 1995 ; Ludescher et al ., 1998 ) and in mice, between 15–50% of CD4 + and 50–90% of CD8 + cells ( Bommhardt et al ., 1994 ; Witkowski et al ., 1994 ). Similarly, mrp1 activity has been detected either on only 3% of CD4 + lymphocytes ( Lohoff et al ., 1998 ; Prechtl et al ., 2000 ), or in the majority of T cells (albeit in the presence of the immunosuppressant FTY720) ( Honig et al ., 2003 ).…”