THE ASSOCIATION of several characteristic chromosomal translocations with various subtypes of acute and chronic myelogenous and lymphocytic leukemias has facilitated the cloning of a number of unique leukemia-associated fusion genes. Characterization of these fusion genes has in turn led to the discovery of previously unrecognized genes. Some of these have now been extensively characterized in vitro, and many encode transcription factors that play important roles in normal hematopoietic development. 1 Recently, the function of several leukemia-associated fusion genes has been investigated using various transgenic murine systems. Despite the generation of acute leukemias in some cases, inconsistent results have made comparisons among different transgenic models problematic. Consequently, fundamental questions remain unanswered about the precise nature of the events leading to the generation of acute leukemias, and the hematopoietic cell type (s) in which such events can occur. The purpose of this perspective is to discuss briefly the potential advantages and disadvantages inherent in various transgenic approaches that are used to model leukemias at the present time, and to discuss future applications of these approaches for achieving a better understanding of the molecular events leading to acute leukemia.

WHAT IS THE TRANSFORMED HEMATOPOIETIC COMPARTMENT (THE CELLULAR ‘‘SOIL’’) OF HUMAN MYELOID LEUKEMIAS? Bonnet and Dick2 have recently demonstrated that transmission of human acute myeloid leukemias (AML) to nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice requires transplantation of a phenotypically immature CD34/38 cell population that comprise a small minority of circulating cells (‘‘SCID-leukemia initiating cells [SL-ICs]). These studies used primary leukemia cells from a variety of AML French-American British (FAB) phenotypic subclassifications (M1, M2, M3, M4, M5). However, cells from patients with the M3 subtype (acute promyelocytic leukemia [APML]) were different, in that M3 SL-ICs were not present in any progenitor fraction (or in unfractionated peripheral blood). These observations suggest that for most AML subtypes, a relatively primitive cell is the target of leukemic transformation, regardless of the extent and lineage of differentiation observed in the majority of leukemic cells present in the peripheral circulation. Given the