Ex vivo mouse models generated for understanding developmental mechanisms of leukemia and sarcoma

Abstract

Mouse bone marrow transplantation (BMT) models are powerful tools for investigating the mechanisms of development and malignant progression of acute myeloid leukemia (AML). AML induction is achieved by the purification of hematopoietic stem/progenitor cells (HSPCs) from the bone marrow of wild-type or genetically engineered mice, transduction of leukemia disease genes into HSPCs using retrovirus-mediated gene transfer, and transplantation of transduced cells into lethally irradiated recipients. The models well recapitulate the phenotypes of human AML, and they have been utilized for tracing the developmental of AML and as platforms of novel therapeutics. By generating the Hoxa9- and Meis1-expressing BMT model, we have identified Sytl1, which promotes engraftment to bone marrow and in vivo expansion of leukemic cells, and Trib1, which encodes pseudokinase functioning in C/EBPα degradation and enhancement of ERK phosphorylation. There are some biological analogies between AML and bone and soft tissue sarcoma (BSTS), for example, they are of mesenchymal origin, they show low mutational burdens, and oncogenic transcription factors play an important role in enhancer-reprograming causally associated tumorigenesis. To overcome technical difficulties in modeling BSTS, we purified embryonic mesenchymal cells, introduced sarcoma-specific fusion genes into the cells, and transplanted them into allogenic hosts. We have succeeded in generating six model lines and are investigating the molecular mechanisms of sarcomagenesis and functions of fusion gene products. In this review, we describe the principle of model generation and novel insights into the molecular mechanisms of leukemia and sarcoma development, which were clarified by analyzing the models.