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Thomas Jefferson University - Arthur M. Buchberg, Ph.D.
Arthur M. Buchberg, Ph.D.

Microbiology & Immunology
Thomas Jefferson University
Jefferson Medical College
Department of Microbiology and Immunology
Associate Professor

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Mailing Address
233 South 10th Street
Philadelphia, Pennsylvania 19107
United States
Contact Information
Phone: 215-503-4533
Fax: 765-807-4239
buchberg@mail.jci.tju.edu
Qualifications
Ph.D.

Expertise and Research Interests
My research interests lab are focused on the molecular genetics of tumor predisposition and development. We continue to work in two model systems. The first is the characterization of homeobox genes involved in myeloid leukemia. We identified several novel oncogenes involved in myeloid leukemia of BXH-2 mice. Nearly 100% of BXH-2 mice develop an aggressive acute myeloid leukemia (AML) by 1 year of age with an average age of onset of 6 months. This leukemia is caused in part by the insertional alteration of cellular protooncogenes or tumor suppressor genes by an endogenous retrovirus. We isolated a common site of viral integration, Meis1, which is activated in 15% of the myeloid tumors. Meis1 encodes a novel homeobox protein and its homeodomain is closest in homology to the homeodomain of PBX1. Our recent work has focused on the characterization of Meis1 as both an oncogene and a pro-apoptotic gene. We recently discovered an apparent paradox concerning the functioning of Meis1. It is clear that the overexpression of Meis1 in conjunction with some Hox proteins induces a rapid and fatal myeloid leukemia; in fact, it has been shown that the overexpression of Meis1 and HoxA9 is a direct consequence of ALL1 (MLL1) fusion proteins resulting from chromosomal translocations in pediatric AMLs. However, we discovered that the overexpression of Meis1 alone, induces a rapid apoptotic response in cells. Our recent studies have focused on exploring the role of Meis1 expression in contributing to cell-death. We have determined that transient expression of Meis1 in a variety of cell lines induces a rapid apoptotic death. This death is abrogated through the coexpression of HoxA9 or HoxA7 (a key cofactor in the development of leukemia) or through deletion of the Meis1 domain required for Meis-Pbx interaction. Cell death is dependent upon caspase 3 and caspase 8. While exploring the pathway and downstream targets of Meis1 induced apoptosis, we have begun to develop strategies to take advantage of the bifurcated mechanism of Meis 1 action. We have recently asked whether we can make use of Meis1-mediated apoptosis to alter the fate of AML cell lines that are already expressing Meis1 and HoxA9 as a consequence of ALL1/MLL translocations. By altering the expression of HoxA9 in these AML cells through the use of siRNA, we have been able to induce apoptosis, presumably through the unbalanced expression of Meis1. We are currently dissecting the mechanism of this proapoptotic response of the AML cells and exploring ways to develop this strategy into a new therapeutic regimen to combat AML.
The second model system we are studying is the influence of genetic modifier loci on the incidence of polyp development in colon cancer. This project is being performed in collaboration with the laboratory of Dr. Linda Siracusa. Mutations in the APC gene are responsible for various familial and sporadic colorectal cancers. Min mice carry a mutation in the homolog of the Apc gene and develop multiple adenomas throughout their small and large intestine. Mapping studies have identified a locus, Mom1, which maps to the distal region of chromosome 4 that dramatically modifies Min-induced tumor number. We have identified a candidate gene for Mom1. The gene for secretory type II Phospholipase A2 (Pla2g2a) maps to the same region that contains Mom1, and we have identified a 100% concordance between allele type and tumor susceptibility. Expression analysis revealed that Mom1 susceptible strains are null for Pla2g2a activity. Our results indicate that Pla2g2a acts as a novel gene which modifies polyp number by altering the cellular microenvironment within the intestinal crypt. We are in the process of determining the mechanism by which Pla2g2a acts to confer resistance to polyp formation as well as to determine the role of Pla2g2a in the development of human colon cancer. We have also identified a new modifier locus, Mom2. Initial studies have revealed that Mom2 is a more potent modifier of intestinal polyp formation, reducing polyp load 85-95% when compared with control mice. Mom2 arose as a spontaneous mutation in one strain of mice. We have refined the location of Mom2 to a 1 Mb gene rich region of mouse chromosome 18. We have recently identified a candidate gene responsible for the Mom2 mutation. We are in the process of confirming the candidate genes role in polyp development. Work is continuing to identify and characterize additional modifier loci that are present within the C3H and CAST genomes that exert profound influences on polyp development. As we identify these modifier genes in the mouse we are exploring their role in the development of human colorectal cancer as both a predictor of disease incidence as well as response to chemotherapeutic regimen. In addition, the identification of new modifier genes could eventually be used to develop new therapeutic strategies against colorectal cancer.
Keywords
Cancer Biology; Cancer Genetics; Mouse Genetics; Molecular Cloning; Modifier Genes; Myeloid Leukemia; Colon Cancer; Mouse Models of Human Disease; Functional Genomics; Insertional Mutagenesis; Sensitized Screens
Publications
  • Wermuth, P. and Buchberg, A.M. Meis1 Mediated Apoptosis is Caspase Dependent and can be Suppressed by Coexpression of HoxA9 in a Human Hematopoietic Cell Lines. Blood 105:1222-1230, 2005
  • Siracusa, L.D., Silverman, K.A., Koratkar, R., Markova, M. and Buchberg, A.M. Genome-wide modifier screens: How the genetics of cancer penetrance may shape the future of prevention and treatment. In Oncogenomics: Molecular Approaches to Cancer (C. Brenner and D. Duggan, ed) John Wiley & Sons, Inc. New York (p255-290)2004.
  • Koratkar, R., Silverman, K.A., Pequignot, E., Hauck, W.W., Buchberg, A.M. and Siracusa, L.D. Analysis of reciprocal congenic strains reveal the C3H/HeJ genome to be highly resistant to ApcMin intestinal tumorigenesis. Genomics 84: 844-852, 2004.
  • Silverman, K.A., Koratkar, R., Siracusa, L.D. and Buchberg, A.M. Exclusion of Madh2, Madh4 and Madh7 as Candidates for the Modifier of Min2 (Mom2) Locus. Mamm. Gen. 14(2):119-29, 2003.
  • Sollars, V.E., McEntee, B.J, Engiles, J.B., Rothstein, J.L. and Buchberg, A.M. A novel transgenic line of mice exhibiting autosomal dominant recessive male-specific lethality and NAFLD. Hum. Mol. Gen 11: 2777-2786, 2002.
  • Maeda R., Ishimura, A., Mood, K., Park,E.K., Buchberg, A.M. and Daar IO. Xpbx1b and Xmeis1b play a collaborative role in hindbrain and neural crest gene expression in Xenopus embryos. Proc. Natl. Acad. Sci.(USA), 99:5448-53, 2002.
  • Silverman, K.A., Koratkar, R., Siracusa, L.D. and Buchberg, A.M. Identification of the Modifier of Min 2 (Mom2) locus and its influence on Apc-induced intestinal neoplasia. Genome Research 12:88-97, 2002.

Individual Expertise profile of Arthur M. Buchberg, Ph.D., Copyright © Arthur M. Buchberg, Ph.D..
Last Updated by Arthur Buchberg, Ph.D. : Friday, September 18, 2009 11:19:55 AM



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