For many years, the Ley lab has used mouse models of AML to establish key principles of AML pathogenesis. The lab established that the initiating event for Acute Promyelocytic Leukemia is the PML-RARA fusion gene created by the t(15;17) that is found in nearly all patients with this disease. The roles of cooperating mutations and the cellular milieu for APL pathogenesis have also been established. In collaboration with the McDonnell Genome Institute at Washington University, the investigators of the Genomics of AML Program Project Grant (PPG- TJ Ley, PI) sequenced the first human cancer genome (a patient with AML) and the first mouse cancer genome (from the mouse model of APL) and have discovered several new recurrent mutations that are important for AML pathogenesis and outcomes, including recurring mutations in DNMT3A and IDH1/2, among many others. These data are now being correlated to RNA expression, DNA methylation, histone modifications and chromatin structure, protein abundance and modification, and clinical datasets. Mouse models of epigenetic modifier mutations in AML are now being created and analyzed. These efforts will hopefully lead to new tests to better establish prognosis, and new approaches for the therapy of patients with this disease.
Model for evolution of genetic changes in acute myeloid leukemia
A hypothetical model in which nonpathogenic somatic mutations (1–3) acquired over the lifespan of a stem cell are propagated in the malignant clone after it acquires a critical initiating mutation (4). Mutation 5 is a progression mutation that cooperates with the AML-initiating mutation 4 to contribute to AML development. Other mutations (represented by 6 and 7) do not cooperate with the AML-initiating mutation 4, and do not contribute to AML development. These subclones are lost, or fail to expand to the limit of detection by sequencing studies.
AML: Acute myeloid leukemia; HSC: Hematopoietic stem cell.
From: Walter MJ, Graubert TA, DiPersio JF, Mardis ER, Wilson RK, Ley TJ
Next-generation sequencing of cancer genomes: back to the future.
Per Med 2009 Nov 1;6(6):653