Immunology Graduate Group
John Kim Choi, M.D., Ph.D.
Department of Pathology and Laboratory Medicine
Address: 413A Stellar Chance Laboratories
Office Phone: (215) 573-6527
Email: jkchoi@mail.med.upenn.edu
Education:
B.S., Cornell University
M.D., Ph.D., University of Pennsylvania
Research Interest
My long-term goals are to (1) understand how transcription factors determine cell differentiation and (2) apply this knowledge to treat human diseases.
Research Summary
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| Inactive gene versus Active Gene |
The transcription factor E47 is critical for early B cell differentiation and proliferation/survival but is dispensable for other cell lineages; thus E47 represents a potential target for treatment of acute B cell leukemia, a neoplastic proliferation of early B cells. To suppress E47 activity, I have engineered a novel dominant-negative E47 that is inducible by tamoxifen. This construct has been subcloned in a lentiviral vector that allows efficient expression in hemopoietic precursors resulting in suppression of E47 activity and suppression of leukemic B cell growth. Using this system, I will determine how suppressing E47 decreases B cell growth, both normal and neoplastic, and identify down-stream target genes of E47. To determine the potential side effect of targeting E47, I will determine the effects of suppressing E47 on non-B cell hematopoiesis.
E47 promotes B cell differentiation by activating B cell-specific genes, a remarkable process since inactive genes are packaged in a chromatin structure that is presumably inaccessible to transcription factors. In fact, E47 can activate B cell specific genes in non-B cells, a feat that cannot be duplicated by another transcription factor, E2-2, even though both factors bind the same DNA site and have strong sequence homology.
Hence, despite the similarities, E47 contains protein domains functionally different from E2-2. To identify protein domains of E47 that can activate chromatin embedded genes, I will swap portions of E47 with equivalent domains of E2-2, express these chimeric constructs in non-B cells, and measure activation by detecting change in chromatin structure and presence of B cell specific transcripts.
Recent Publications
Choi, J., M. L. Costa, C. S. Mermelstein, C. Chagas, S. Holtzer, and H. Holtzer. 1990. MyoD converts primary dermal fibroblasts, chondroblasts, smooth muscle, and retinal pigmented epithelial cells into striated mononucleated myoblasts and multinucleated myotubes. Pro.Nat. Aca. Sci. 87 (20):7988-92.
Choi, J. K., S. Holtzer, S. A. Chacko, Z. X. Lin, R. K. Hoffman, and H. Holtzer. 1991. Phorbol esters selectively and reversibly inhibit a subset of myofibrillar genes responsible for the ongoing differentiation program of chick skeletal myotubes. Mol. & Cell. Biol. 11 (9):4473-82.
Choi, J.K., C.P. Shen, H.S. Radomaska, L.A. Eckhardt, and T. Kadesch. 1996. E47 activates the Ig-heavy chain and TdT loci in non-B cells. EMBO J. 15 (18):5014-21.
Shick, L., J.H. Carman, J. K Choi, K. Somasundaram, M. Burrell, D.E. Hill, Yi-Xin Zeng, Y. Wang, K.G. Wiman, K. Salhany, T.R. Kadesch, J.G. Monroe, L.A. Donehower, and W.S. El-Deiry. 1997. Decreased Ig deposition in tumors and increased immature B cells in p53-null mice. Cell Growth & Different. 8:121-31.
Tomasz Skorski, Alfonso Bellacosa, Margaret Nieborowska-Skorska, Miroslaw Majewski, Robert Martinez, John K.Choi, Rossana Trotta, Pawel Wlodarski, Danilo Perrotti, Tung O. Chan, Mariusz A. Wasik, Philip N. Tsichlis, and Bruno Calabretta. 1997. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 16:6151-6161.
Salhany KE., Macon WR., Choi JK., Elenitsas R., Lessin SR., Felgar RE., Wilson DM., Przyblski GK., Lister J., Wasik MA., & Swerdlow SH. 1998. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Amer. J. Surg. Path. 22(7):881-93.
Choi JK., J. Kearns, H.I. Palevsky, K.T. Montone, L.R. Kaiser, C.M. Zmijewski, & J.E. Tomaszewski. 1999. Hyperacute rejection of a pulmonary allograft: case report, immediate clinical and pathological findings. Amer. Resp.Crit. Care Med. 160:1015-18.