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Training
- B.Sc., 1973: Hampden-Sydney College, Hampden-Sydney, VA
- M.D., 1977: University of Virginia
- Post Doctoral:1977-1978: Intern, University of Texas Southwestern, Parkland Hospital
- Clinical Associate:1978-1980: Immunology Branch, National Cancer Institute
- Medicine Resident and Hematology/ Oncology Fellow: 1980-1983: University of Virginia
Positions
- Professor of Medicine, 1995-present: Indiana University School of Medicine, Indianapolis, IN.
- Member, 1995-present: WaltherOncologyCenter, Indianapolis, IN.
- Associate Professor of Medicine, 1988-1995: Indiana University School of Medicine, Indianapolis, IN
- Assistant Professor of Medicine, 1983-1988: Indiana University School of Medicine, Indianapolis, IN
Description and summary of research focus of the laboratory:
The efforts of Dr. Boswell's laboratory are focused on basic and applied clinical aspects of leukemia. In the basic area there is a long-term interest in the mechanism of leukemic cell proliferation mediated through the c-myc gene, a gene which is regulated by transcription. Recently, they have identified an important transcriptional pathway regulating the c-myc gene that occurs in leukemic cells which proliferate because they contain the major oncogene of chronic granulocytic leukemia (CGL). That CGL oncogene, BCR-ABL, encodes a cytoplasmic tyrosine kinase oncogene they previously demonstrated to bind to adaptor proteins Grb-2 and Shc, thus leading to p21ras activation and activation of the enzyme phosphatidylinositol-3-kinase (PI-3-kinase). The transcriptional pathway to c-myc gene expression in cells transformed by the oncogene p210 BCR-ABL involves the transcription factor, E2F1. E2F1 is at an end-point of the signaling pathway of p210 BCR-ABL, where it functions on the transcriptional regulatory cis-element of c-myc. In turn, the E2F1 transcription factor is subject to control by the tumor suppressor protein, retinoblastoma (pRb). When pRb is phosphorylated by upstream signals that emanate from BCR-ABL, then E2F1 is released to act on the c-myc promoter cis-element. They have defined two routes to regulation of pRb through its kinase regulator, cdk4. p210 BCR-ABL seems to use the pathway involving p21ras to regulate c-myc through the transcription factor E2F1, because when cyclic AMP is added to cells (known to inhibit the Ras pathway), cdk4 activity is turned off, and E2F1 no longer drives c-myc. This occurs because the "ligand activator" protein for cdk4, cyclin D1, is diminished when cAMP is added in the early G1-phase of the cell cycle. Cyclin D1 is known to be controlled through the p21ras signaling pathway mentioned above. They have also found that the enzyme PI-3-kinase is required for c-myc gene transcription because specific inhibition of PI-3-kinase leads to downregulation of c-myc transcription through the same pathways, but in this case, the content of cyclin D1 is not the main cause of decreased cdk4 function. They are examining the phosphorylation status of cdk4 to understand its regulation through the PI-3-kinase pathway independent of cyclin D1. Regarding applied clinical aspects of leukemia, they have been studying a mechanism by which leukemia cells are rendered intrinsically resistant to the major chemotherapy treatment regimen for acute myeloid leukemia, involving an anthracycline and cytosine arabinoside. One way these drugs kill leukemia cells is by oxidative damage to cells. They have been studying a cellular signaling pathway, which is responsible for two aspects of cellular compensation to oxidative damage (buffering and enzymatic modification of oxyradical-inducing compounds) and for cellular recognition and export of xenobiotics. The central component of this putative pathway is an enzyme responsible for phosphorylating the N-terminal domain of the c-jun transcription factor, c-jun N-terminal kinase or JNK. JNK is a primary sensor for genotoxic and oxidative damage to cells, and is therefore a prime candidate to convey a repair signal. In addition, JNK is constitutively activated by tyrosine kinase oncogenes like p210 BCR-ABL, mentioned above, and by small ras/rho-family G proteins that participate in a variety of leukemias and solid tumors. In preliminary data, a striking correspondence has been found between constitutive activity of JNK in primary blast cells of acute leukemia obtained at diagnosis, and the subsequent failure of induction chemotherapy involving high-dose cytosine arabinoside and daunomycin. It appears that excessive production of c-jun protein as a result of constitutive signaling in the tyrosine kinase-JNK signaling pathway leads to increased production of genes whose transcription is regulated by c-jun, and whose activity in cells involves enzymatic regulation of the cellular redox status and export of toxic chemotherapy drugs. Therefore, constitutive activity of JNK enzyme in leukemia cells lends cellular resistance to chemotherapy drugs. Knowledge of this mechanism should lead to improved treatments by inactivating the resistance mechanism.
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