Cytochrome P450 and drug metabolism in the stem cell niche

Although it is clear that the bone marrow (BM) microenvironment regulates normal and leukemia hematopoietic stem cells (HSC) homeostasis, there is limited knowledge detailing the mechanisms involved. We recently found that the BM niche protects human HSCs from the pro-differentiation effects of retinoic acid (RA) via expression of CYP26, a cytochrome P450 (CYP), RA-metabolizing enzyme (Ghiaur G et al. PNAS 2013). We found that unopposed RA signaling resulted in HSC loss, while inhibition of RA signaling expanded SCID-repopulating cells (SRCs). More so, BM stroma and not human HSCs, expressed CYP26. While BM stroma maintained human SRCs in culture, inhibition of stroma CYP26 resulted in complete loss of SRCs. Even though the majority of AML blasts are sensitive to RA in vitro, RA based therapies have no clinical impact on AML other than acute promyelocytic leukemia (Petrie K et al. Curr Opinion Hem 2009).