Murine Models of Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a phenotypically and genetically heterogeneous hematologic malignancy. Extensive sequencing efforts have mapped the genomic landscape of adult and pediatric AML revealing a number of biologically and prognostically relevant driver lesions. Beyond identifying recurrent genetic aberrations, it is of critical importance to fully delineate the complex mechanisms by which they contribute to the initiation and evolution of disease to ultimately facilitate the development of targeted therapies. Towards these aims, murine models of AML are indispensable research tools. The rapid evolution of genetic engineering techniques over the past 20 years has greatly advanced the use of murine models to mirror specific genetic subtypes of human AML, define cell-intrinsic and extrinsic disease mechanisms, study the interaction between co-occurring genetic lesions, and test novel therapeutic approaches. This review summarizes the mouse model systems that have been developed to recapitulate the most common genomic subtypes of AML. We will discuss the strengths and weaknesses of varying modeling strategies, highlight major discoveries emanating from these model systems, and outline future opportunities to leverage emerging technologies for mechanistic and preclinical investigations.

Keywords: acute myeliod leukemia; AML; KMT2a (MLL) rearrangements; NUP98 fusion; core binding factor acute myeliod leukemia; genetically engineered mice (GEM); patient-derived xenograft (PDX); transgenic mouse.

Figure 1

Summary of commonly used mouse model methods to study acute myeloid leukemia. *Indicates models that independently generate leukemia without cooperating mutations. GEMM, Genetically-engineered mouse model; mHSC, murine hematopoietic stem cell; mES, murine embryonic stem cell; shRNA, short hairpin RNA.