Loss of P-glycoprotein expression in hematopoietic stem cells does not improve responses to imatinib in a murine model of chronic myelogenous leukemia.
Selective inhibition of the BCR/ABL tyrosine kinase by imatinib has become a first-line therapy for chronic myelogenous leukemia (CML). However, BCR/ABL-positive progenitors often persist despite treatment, and relapse associated with resistance to imatinib has been described in many patients with advanced disease. Drug efflux by P-glycoprotein (P-gp), as well as point mutations in BCR/ABL oncoprotein, has been implicated in the mechanism of resistance to imatinib. In this study, we established a murine transplantation model of CML-like myeloproliferative disease using Mdr1a/1b-null mice and analyzed the effects of loss of P-gp on resistance to imatinib. We found that mice transplanted with Mdr1a/1b-null bone marrow (BM) that had been transduced with a BCR/ABL retroviral vector displayed similar responses to imatinib, compared with those transplanted with BCR/ABL-transduced wild-type BM. In the absence of P-gp, the incidence and latency of disease in secondary recipients was not changed in imatinib-treated mice, relative to wild-type controls. Furthermore, K562 cells engineered to overexpress P-gp remained sensitive to imatinib-induced growth inhibition and cell death. Together, our findings suggest that P-gp expression in hematopoietic stem cells does not significantly contribute to imatinib resistance in CML.
Division of Experimental Hematology, Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Y
Y
Zong
S
S
Zhou
B P
BP
Sorrentino
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001549:Benzamides; D016026:Bone Marrow Transplantation / Q000379:methods; D002470:Cell Survival / Q000187:drug effects; D017690:Cell Transplantation; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016019:Survival Analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate