The prospects for long-term survival of patients, both adults and children, with acute myeloid leukemia (AML) are poor. The response to therapy is often variable and many studies are focusing on pharmacogenetic differences in metabolism and transport of drugs to account for poor response. A complementary approach in AML is to identify key metabolism and transporter differences and then target these potential points of vulnerability with drugs to improve therapeutic outcome. In both pediatric and adult AML, MYCN is frequently upregulated. Among AML patients with increased MYCN expression, a porphyrin transporter (ABCG2) is upregulated along with the heme/porphyrin metabolic pathway. There is no treatment in MYCN- driven AML that is directed towards these metabolic changes. Our promising preliminary data show that survival of MYCN-driven leukemic progenitors is negatively impacted when porphyrin metabolism is disrupted by either chemical inhibition or deletion of the ABC transporter, ABCG2. This indicates that porphyrin export by ABCG2 is required for self-renewal of leukemic progenitors. We propose three sets of highly integrated studies that will test our central hypothesis that ABCG2 transporter mediated regulation of porphyrin metabolism is crucial for survival of MYCN-driven leukemic progenitors and blasts. (1) Using in vitro and in vivo AML models, we will investigate the relationship between porphyrin metabolism, ABCG2 expression and function, and leukemic progenitor survival. (2) Using high- throughput screening, we will identify novel inhibitors of ABCG2 that impact both catalytic activity and subcellular location. (3) Elucidate how excess porphyrins produce cell death focusing on pathways that involve the glutathione pathway as well as anti-apoptotic pathways. These studies of the porphyrin transporter, ABCG2, in the context of MYCN-driven AML, provide a unique opportunity to develop new knowledge and improve therapy.

Public Health Relevance

MYCN-driven acute myeloid leukemia (AML) has alterations in transport and metabolism. Our investigations are likely to uncover new and more efficacious therapeutic approaches to facilitate treatment of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA194057-03
Application #
9230351
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Mufson, R Allan
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Wijaya, Juwina; Fukuda, Yu; Schuetz, John D (2017) Obstacles to Brain Tumor Therapy: Key ABC Transporters. Int J Mol Sci 18:
Fukuda, Yu; Wang, Yao; Lian, Shangli et al. (2017) Upregulated heme biosynthesis, an exploitable vulnerability in MYCN-driven leukemogenesis. JCI Insight 2:
Liu, Chengcheng; Janke, Laura J; Yang, Jun J et al. (2017) Differential effects of thiopurine methyltransferase (TPMT) and multidrug resistance-associated protein gene 4 (MRP4) on mercaptopurine toxicity. Cancer Chemother Pharmacol 80:287-293
Nakanishi, Takeo; Ohno, Yasuhiro; Aotani, Rika et al. (2017) A novel role for OATP2A1/SLCO2A1 in a murine model of colon cancer. Sci Rep 7:16567
Morfouace, Marie; Cheepala, Satish; Jackson, Sadhana et al. (2015) ABCG2 Transporter Expression Impacts Group 3 Medulloblastoma Response to Chemotherapy. Cancer Res 75:3879-89