Expression of MDR1 by normal bone marrow cells and its implication for leukemic hematopoiesis

Expression of MDR1 is a well-characterized mechanism leading to resistance of tumor cells to drugs like vinca-alkaloids, anthracyclines, and epipodophyllotoxins. In hematopoiesis, recent data indicate that not only leukemic cells, but also some populations of normal hematopoietic cells, particularly CD34+ progenitor cells as well as peripheral blood lymphocytes, express a functional multidrug-resistant phenotype. Among CD34+ cells, we found evidence that myeloid committed precursor cells (CD34+CD33+ have lower levels of MDR1 expression than earlier CD34+ cell populations, but there was no difference in MDR 1 expression between CD34+HLA-DR- and CD34+HLA-DR+ sub-populations. During normal myeloid differentiation, MDR1 expression is down-regulated, which is similar to our observations in acute myelogenous leukemia (AML): MDR 1 expression was only rarely detected in acute promyelocytic leukemia, which was in contrast to other subtypes of AML; also, within leukemic subpopulations of the same patient, higher MDR 1 levels were correlated with a more immature immunophenotype. Regarding regulation of MDR 1 expression, we did not observe changes of MDR 1 expression in normal CD34+ cells in response to various cytokines. However, in 2 patients with AML treated with interleukin-3 and granulocyte-colony stimulating factor, respectively, a significant down-regulation of MDR1 expression was found after 24 hours. In conclusion, there is evidence that the pattern of MDR 1 expression observed in leukemias reflects the distribution of MDR1 in normal hematopoiesis. In contrast to normal CD34+ cells, leukemic cells from some AML patients can respond to cytokines with a down-regulation of MDR 1, which may contribute to response to cytokine/chemotherapy combinations.