All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment.
All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment.
复制标题
DOI：
10.1371/journal.pone.0127790
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ghiaur G
中科院分区：
文献类型：
--
作者：
Su M;Alonso S;Jones JW;Yu J;Kane MA;Jones RJ;Ghiaur G
Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA-induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML.
登录
查看更多内容
影响因子：
20.3
作者：
Burnett, Alan K.;Hills, Robert K.;Gale, Rosemary E.
通讯作者：
Gale, Rosemary E.
影响因子：
56.9
作者：
Bowles, J;Knight, D;Koopman, P
通讯作者：
Koopman, P
影响因子：
6.2
作者：
Burnett, Alan K.;Milligan, Donald;Wheatley, Keith
通讯作者：
Wheatley, Keith
影响因子：
2.7
作者：
Lehmann, S;Bengtzen, S;Paul, C
通讯作者：
Paul, C
影响因子：
20.3
作者：
Milligan, Donald W.;Wheatley, Keith;Burnett, Alan K.
通讯作者：
Burnett, Alan K.