Expression of multidrug resistance 1 gene in association with CXCL12 in chronic myelogenous leukaemia.
Even though the BCR-ABL tyrosine kinase inhibitor imatinib significantly improves the prognosis of chronic myelogenous leukaemia (CML) patients, drug resistance is a major obstacle to better management. We examined the interaction of recently defined bone marrow microenvironment factors CXCL12 and ATP-binding cassette (ABC) transporters in the bone marrow of CML patients in the chronic phase and blast crisis.Expression levels of mRNA extracted from frozen specimens of CML patients were measured by real-time polymerase chain reaction. The expression of the ABC transporters MDR1, ABCC1, ABCG2, and CXCL12 was significantly higher in the bone marrow samples of CML blast crisis than in those of CML chronic phase. Immunohistochemical staining for CXCL12 revealed that the proportion of CXCL12 positive reticular cell areas correlated well with the mRNA levels of CXCL12 in CML bone marrow. Finally, co-culture experiments of K562 CML cells with CXCL12 expressing mesenchymal cells (OP9 cells or human CXCL12 transfected 3T3 cells) revealed enhanced mRNA levels for MDR1 in a CXCL12 rich environment.These results suggest that imatinib treatment restores the bone marrow microenvironment in CML with the presence of CXCL12 expressing reticular cells but in turn induces the overexpression of MDR1 in haematopoietic cells due to up-regulated expression of CXCL12.
1Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 2Department of Internal Medicine, Japan Red-Cross Medical Center, Tokyo 3Department of Pathology 4Department of Internal Medicine, National Hospital Organization Kumamoto Medical Center, Kumamoto, Japan.
Iichiroh
I
Onishi
Yasunori
Y
Nakagawa
Toshihiko
T
Murayama
Michihiro
M
Hidaka
Kouhei
K
Yamamoto
Shiho
S
Abe-Suzuki
Shinya
S
Abe
Morito
M
Kurata
Masanobu
M
Kitagawa
D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D001853:Bone Marrow / Q000378:metabolism; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000235:genetics*; D018920:Coculture Techniques; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001549:Benzamides; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate