title: OCT-1, ABCB1, and ABCG2 Expression in Imatinib-Resistant Chronic Myeloid Leukemia Treated with Dasatinib or Nilotinib.
abstract: This study explored drug transporter expression levels and their impact on clinical response to imatinib and second-generation tyrosine kinase inhibitors (TKIs) in imatinib- resistant chronic myeloid leukemia (CML). Imatinib-resistant chronic phase CML patients treated with dasatinib (n=10) and nilotinib (n=12) were enrolled. The mRNA expression of the OCT-1, ABCG2, and ABCB1 genes was quantified by using paired bone marrow samples obtained before administering imatinib and at the point of detecting imatinib resistance (just before starting second-generation TKIs). The expression levels of OCT-1 and ABCG2 were lower in follow-up than in imatinib-naïve samples. ABCB1 revealed highly variable expression levels before and after imatinib treatment. In addition, median ABCB1 expression in follow-up samples was lower in patients achieving complete cytogenetic response or major molecular response during imatinib treatment than in failed patients. Higher ABCG2 expression in imatinib-exposed samples showed a negative impact on optimal response to dasatinib. Patients with higher ABCG2 expression in imatinib-exposed samples also had shorter progression- free survival with dasatinib treatment. However, no significant correlation was found between these drug transporter expression levels in imatinib-naïve or imatinib- exposed samples and responses to nilotinib. In imatinib-resistant CML, OCT-1 and ABCG2 mRNA expression decreased after imatinib treatment. Patients with higher ABCG2 expression in imatinib-exposed samples showed poor treatment outcome with dasatinib. On the other hand, a higher expression level of ABCB1 in imatinib-exposed samples did not affect second-generation TKI responses but was correlated with poor imatinib responses.
authors.affiliation: Department of Hematology-Oncology, Hematology Clinics, Chonnam National University Hwasun Hospital, Gwangju, Korea.
authors.forename: Yeo-Kyeoung
authors.initials: YK
authors.lastname: Kim
authors.affiliation: Department of Hematology-Oncology, Hematology Clinics, Chonnam National University Hwasun Hospital, Gwangju, Korea.
authors.forename: Seung-Shin
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Department of Hematology-Oncology, Hematology Clinics, Chonnam National University Hwasun Hospital, Gwangju, Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Jeong
authors.affiliation: Department of Hematology-Oncology, Hematology Clinics, Chonnam National University Hwasun Hospital, Gwangju, Korea.
authors.forename: Jae-Sook
authors.initials: JS
authors.lastname: Ahn
authors.affiliation: Department of Hematology-Oncology, Hematology Clinics, Chonnam National University Hwasun Hospital, Gwangju, Korea.
authors.forename: Deok-Hwan
authors.initials: DH
authors.lastname: Yang
authors.affiliation: Department of Hematology-Oncology, Hematology Clinics, Chonnam National University Hwasun Hospital, Gwangju, Korea.
authors.forename: Je-Jung
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Myung-Geun
authors.initials: MG
authors.lastname: Shin
authors.affiliation: Department of Hematology-Oncology, Hematology Clinics, Chonnam National University Hwasun Hospital, Gwangju, Korea. ; Genome Research Center for Hematopoietic Diseases, Chonnam National University Hwasun Hospital, Hwasun, Korea.
authors.forename: Hyeoung-Joon
authors.initials: HJ
authors.lastname: Kim
keywords: ABCB1 protein; ABCG2 protein; Imatinib; Myeloid leukemia