Pharmacogenetics of Alkylator-Associated Acute Myeloid Leukemia

Abstract

Therapy-related acute myeloid leukemia (t-AML) is a lethal late complication of alkylator chemotherapy. The genetic basis of susceptibility to t-AML is poorly understood. Both t-AML and de novo AML are complex genetic diseases, requiring cooperating mutations in interacting pathways for disease initiation and progression. Germline variants of these ‘leukemia pathway‘ genes may cooperate with somatic mutations to induce both de novo and therapy-related AML. Several cancer susceptibility syndromes have been identified that cause an inherited predisposition to de novo and t-AML. The genes responsible for these syndromes are also somatically mutated in sporadic AML. We reason that germline polymorphism in any gene somatically mutated in AML could contribute to t-AML risk in the general population. Identification of these susceptibility alleles should help clinicians develop tailored therapies that reduce the relative risk of t-AML.

Keywords: :

• acute myeloid leukemia
• alkylator
• CEBPA
• chemotherapy
• Fanconi anemia
• GATA1
• NF1
• pharmacogenetics
• PTPN11
• PU.1
• RAS
• RUNX1
• single nucleotide polymorphism
• TP53
• WT1

Acknowledgments

Supported by grants from the National Institutes of Health (P01 CA101937) and the Barnes Jewish Hospital Foundation. Derek Van Booven provided expert informatics support.

Additional information

Funding

Supported by grants from the National Institutes of Health (P01 CA101937) and the Barnes Jewish Hospital Foundation. Derek Van Booven provided expert informatics support.