Eric Y. Chen 1989-1999
Oncology Fellow
University of Washington, Fred Hutchinson Cancer Research Center
University of Wisconsin - Madison 1989
Human Oncology PhD 1997
Steven Clark
ABL transformation of lymphocyte progenitors
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The preferential ability of the ABL oncogene to transform immature B-cells in vitro has served as a useful system for studying B-lymphopoiesis. We hypothesized that ABL could be used to establish an analogous system to transform immature T-cells in vitro for studying T-lymphopoiesis; however, we could not establish such a system. Thus, we used an in vivo method to transform immature T-cells by inducing thymomas with the v-abl expressing Abelson murine leukemia virus (A-MuLV). However, thymomas contained an B220+ Thy-1lo population, which expressed an early lymphoid phenotype. The B220+ Thy-1lo thymoma cells also did not rearrange TCR or Igk genes, but contained a subpopulation of early B-cells that rearranged Igh genes. However, in 6 of 13 tumors, 40-70% of the B220+ Thy-1lo thymoma cells did not rearrange Igh genes, and appear to represent undifferentiated lymphoid progenitors.
We next sought to identify the thymic target population that gave rise to the B220+ Thy-1lo undifferentiated lymphoid progenitors. Since the B220+ Thy-1lo thymoma population phenotypically resembled the B220+ Thy-1lo bone marrow population that is the preferential population phenotypically resembled the B220+ Thy-1lo bone marrow population that is the preferential A-MuLV transformation target in vitro, we tested the hypothesis that the normal thymus also contains B220+ Thy-1lo cells that are highly susceptible to in vitro A-MuLV transformation. Although B220+ cells (1/3 of which were Thy-1lo) were found in the thymus, thymic B220+ cells were unlike marrow B220+ cells since they were not susceptible to in vitro A-MuLV transformation and were not enriched with actively cycling cells. Therefore, thymic B220+ cells likely do not contain the target that gives rise to the undifferentiated lymphoid progenitors.
Finally, we started examining how the ABL oncogenes may interfere with early B-lymphopoiesis. v-abl transformed pre-B cell lines typically can not rearrange Ig light chain genes since the v-abl kinase actively suppresses RAG expression and NF-kb activity. BCR-ABL transformed pre-B cells commonly do not rearrange Igk light chain genes also; therefore, we hypothesized that v-abl and BCR-ABL may utilize similar mechanisms to arrest Ig light chain assembly. We found that BCR-ABL kinase activity is necessary for RAG inhibition; however, kinase activity is not sufficient for RAG suppression since other BCR-ABL domains are also involved. |
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| Thesis Publications |
- Chen EY, Swanson BJ, Clark SS. Transformation of undifferentiated Thy-1 B220+ thymic lymphoid cells by the Abelson murine leukemia virus. Dev Immunol 8:1-18, 2000.
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