The study of myeloid leukemia induced by slow transforming murine leukemia viruses (MuLV) in the laboratory mouse has led to discovery of many important genes with critical roles in regulating the growth, death, lineage determination and development of hematopoietic precursor cells. This review provides an overview of the susceptible strains and virus isolates that cause acute myeloid leukemia (AML) in mice. In addition, newer methodologies, involving the use of the polymerase chain reaction, that have been used to identify cancer genes mutated by proviral insertion in mouse models, will be discussed. As cancer is a multi-gene disease, a system in which pairs of oncogenic mutations are classified as redundant, neutral or synergistic is described. The potential to combine MuLV mutagenesis with recent advances in mouse transgenesis in order to model specific forms of myeloid leukemia or genetic pathways common in human AML will be discussed. Finally, a general strategy for maximizing these genetically rich models to foster a better understanding of AML physiology and developing therapies is proposed. Leukemia (2000) 14, 1174-1184. Keywords: acute myeloid leukemia; mouse; MuLV; molecular cloning
MuLV-induced AMLSeveral excellent reviews have been published which describe MuLV-induced leukemia [1][2][3][4][5][6] or mouse models of AML.
7-9Therefore, only a brief summary of the diversity of mouse strains and virus combinations that result in AML is in order. For the purposes of this review, acute erythrocytic and megakaryocytic leukemias are not considered; instead, the focus is on AML representing earlier progenitors or neutrophil and monocyte/macrophage progenitors. It had been shown that various MuLV could induce non-B, non-T cell leukemia in susceptible mice by the early 1980s. [10][11][12][13][14][15] It was shown that these leukemias consisted of cells in various myeloid lineages and stages of maturation. Criteria for classification of myeloid leukemia in mice have included lack of B or T cell antigen receptor gene rearrangements, 16,17 myeloid esterase staining, 11 cell and nuclear morphology, 13,18 induction of differentiation to mature myeloid cell types and expression of lineage-specific genes or cell surface markers. 15,19 A system of classification of human AML into subtypes, called the French-American-British (FAB) system, 20,21 has proved useful in distinguishing AML according to many important clinical phenotypes such as prognosis, response to various therapies, development of intercurrent problems, and Table 1). The FAB subclassifications are based primarily on morphological appearance, myeloid esterase staining, and expression of cell surface markers. To some extent, specific genetic changes, such as chromosomal translocations, tend to cluster within a FAB subtype of AML, indicating that these definitions do indeed reflect basic genetic differences between subtypes that probably dictate their behavior. A good example of this is the strong correlation between translocations involving the retinoic ac...