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We have shown that the critical drug metabolizing enzymes cytochrome P450 (CYP) 3A4 and cytidine deaminase (CDA) are highly expressed by BM stroma, and play an important role in this resistance to chemotherapy. However, what factors influence the chemoprotective capacity of the BM microenvironment, specifically related to CYP3A4 and CDA expression, are unknown. In this study, we found that the presence of AML cells decreases BM stromal expression of CYP3A4 and CDA, and this effect appears to be at least partially the result of cytokines secreted by AML cells. We also observed that stromal CYP3A4 expression is up\u2010regulated by drugs commonly used in AML induction therapy, cytarabine, etoposide and daunorubicin, resulting in cross\u2010resistance. Cytarabine also up\u2010regulated CDA expression. The up\u2010regulation of CYP3A4 associated with disease control was reversed by clarithromycin, a potent inhibitor of CYP3A4. Our data suggest that minimal residual disease states are characterized by high levels of stromal drug metabolizing enzymes and thus, strong microenvironment\u2010mediated drug resistance. These results further suggest a potential role for clinically targeting drug metabolizing enzymes in the microenvironment.<\/jats:p>","DOI":"10.1111\/jcmm.14298","type":"journal-article","created":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T13:18:04Z","timestamp":1553779084000},"page":"4111-4117","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Regulation of drug metabolizing enzymes in the leukaemic bone marrow microenvironment"],"prefix":"10.1111","volume":"23","author":[{"given":"Meng","family":"Su","sequence":"first","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Ting","family":"Chang","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University Baltimore 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