The Oncogenic Potential of BCRABL

Most of our understanding of the transforming capabilities of BCR-ABL has been generated from in vitro assays using factor-dependent hematopoietic cell lines or fibroblasts. However, the in vitro models have limitations; they frequently provide contradictory results and they do not provide the means to further study the pathogenetic mechanisms that are linked to the expression of BCR-ABL. Lacking functional assays using human cells has led to the development of murine CML models to recapitulate the manifestations of the disease.

In vivo animal systems include the use of transgenic mice and retroviral transduction models.33,34 In a transgenic mouse model, Hariharan and colleagues explored the biological effects of the BCR-v-ABL gene that they introduced into the mouse germ line under the control of the immunoglobulin heavy chain enhancer elements or a retroviral long terminal repeat of the myeloproliferative sarcoma virus.35 Although the transgenic mice develop multiple hematologic neoplasms, they are rarely myeloid and do not recapitulate the characteristics of chronic phase CML in humans. Expression of pi90BCR-ABL DNA generated myeloid and lymphoid acute leukemias supporting the evidence of a causative relationship between Ph and human leukemias. However, most of the transgenic mice in these models fail to recapitulate a myeloproliferative disease state and are therefore unsuitable to be used as models for human CML.36,37

Recently, expression in the progeny of transgenic mice of p210BCR-ABL driven by the promoter of the TEC gene was demonstrated to generate a myeloproliferative disorder resembling CML.38 However, the penetrance of this event is undetermined and the latency period of the disease was greater than 1 year.

A more successful approach in recapitulating human CML has been expression of p210BCR-ABL in murine bone marrow cells by retroviral transduction.39-42 In these models, infection of murine bone marrow cells with a retrovirus encoding p210BCR-ABL and subsequent transplantation into lethally irradiated syngeneic recipients caused a syndrome that closely resembled the chronic phase of human CML. The mice developed high white blood cell counts, splenomegaly, and extramedullary hematopoiesis, and, in some instances, showed progression from chronic to blastic phase. Limitations of these models include difficulties in generating high-titer BCR-ABL expressing retroviruses, a low incidence of the myeloproliferative disease in transplant recipients, and a low frequency of serial transfer of the myeloproliferative disease. Recently, several investigators have described a new murine CML model in which p210BCR-ABL was expressed in bone marrow cells of mice by retrovirus transduction using a murine stem cell vector (MSCV). This model was able to induce a myeloproliferative disease resembling human CML in all mice with a short latency period of 3 to 4 weeks, thus providing a useful CML animal model for future studies.43,44

Although it has been suggested that the acquisition of Ph may not be the first clonal event in CML leukemogenesis and that the Ph-positive clone, at least in some cases, may arise by subclone formation, the fact that virtually all patients in chronic phase are Ph-positive and the combined data from animal experiments lend significant weight to the pathogenetic role of BCR-ABL as central mediators of myeloid proliferation and transformation in CML.

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