Murine Models Of Bcr AblPositive Leukemia

In a seminal study Daley and colleagues showed that transplantation of murine bone marrow infected with a Bcr-Abl retrovirus into lethally irradiated syngeneic recipients induced a myeloproliferative syndrome that resembled human CML.4 This study provided strong evidence that Bcr-Abl is the causative agent responsible for CML and suggested that no additional abnormalities are required for leukemogenicity. However, disease pen-etrance with the model was relatively low. In addition, a proportion of mice developed atypical Bcr-Abl-posi-tive tumors, such as macrophage tumors. Subsequent studies showed that the conditions used for retroviral infection of murine bone marrow greatly impact the phenotype of the disease.127 For example, mice transplanted with marrow harvested from donor mice not treated with 5-fluorouracil almost invariably develop B-cell ALL, not a myeloproliferative syndrome. Another important variable is the promoter used to drive the expression of Bcr-Abl. Thus, a more recently developed model uses the promoter of the murine stem cell leukemia and employs high viral titers for transduc-tion.128 With this approach, 100% of animals develop a myeloproliferative syndrome resembling CML with a latency of approximately 25 days. Although the refinements to the murine disease model have greatly increased its usefulness, one remaining concern is that the Bcr-Abl-positive myeloproliferative syndrome, though phenotypically resembling chronic phase CML, is in reality a very aggressive and rapidly lethal leukemia, in contrast to the chronic phase of human CML. This may be due the fact that levels of Bcr-Abl protein are much higher than in human CML cells.

Transgenic approaches placing Bcr-Abl under the control of the Bcr promoter were initially not successful, due to embryonic lethality.129 However, with the use of a tetracycline-repressible system and enhancer elements of the SCL locus, it has recently been possible to generate transgenic mice that develop a myeloproliferative syndrome that reproduces some of the features of chronic phase CML and is reversible on re-exposure to tetracyclin.130

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