ROLE OF CYTOCHROME P450 IN FLT3/ITD ACUTE MYELOID LEUKEMIA BONE MARROW MICROENVIRONMENT

Internal tandem duplications (ITDs) in Fms-like tyrosine kinase 3 (FLT3) are frequent mutations in acute myeloid leukemia (AML), and are associated with inferior outcomes. Although FLT3 tyrosine kinase inhibitors (TKIs) provide clinical benefits, drug resistance is a common problem, and relapse remains the major hurdle toward a cure for FLT3/ITD AML. To better understand the mechanisms of drug-resistance, this project aimed to identify the factors responsible for bone marrow (BM)-mediated drug resistance in FLT3/ITD AML. Specifically, the focus was on the roles of two cytochrome P450 (CYP) enzymes expressed in bone marrow stromal cells (BMSCs). In Chapter 2, we found that BM stromal CYP3A4, the major xenobiotic-metabolizing enzyme involved in chemotherapy, including FLT3 TKIs, inactivation, contributes to FLT3 TKI resistance in FLT3/ITD AML. We demonstrated that inhibiting BM stromal CYP3A4 restored FLT3 inhibition and anti-leukemic activity of FLT3 TKIs in the presence of BMSCs. In Chapter 3, we identified BM stromal CYP26, the predominant enzyme responsible for inactivating retinoic acid (RA), confers resistance to FLT3 TKI and all-trans retinoic acid (ATRA) combination treatment in FLT3/ITD AML. This resistance is at least partially the result of CYP26-mediated RA metabolism, and is largely regulated by the CYP26B1 isoenzyme. By inhibiting or bypassing CYP26, we showed that BMSC-mediated protection of FLT3/ITD AML against the combination treatment was abrogated. Finally, we also found that BM stromal CYP26 appears to play a role in FLT3 TKI resistance even without exogenous ATRA treatment. Overall, our studies indicate that CYP enzymes confer drug resistance in the FLT3/ITD AML BM microenvironment. Therefore, inhibiting CYPs or bypassing CYP-mediated drug inactivation in the BM are potential strategies to overcome drug resistance and improve FLT3/ITD AML treatment