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| Dr. Buchberg’s research interests focus on the molecular genetics of leukemia and cancer susceptibility. Currently, Buchberg’s group is using two model systems. The first is the identification of genes involved in myeloid leukemia, using BXH-2 mice. Nearly 100% of BXH-2 mice develop an aggressive acute myelogenous leukemia (AML) by one 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. Buchberg and his group are characterizing the genes that are sites of viral integration to determine their role in contributing to leukemia. They have recently isolated a new common site of viral integration, Meis1, that is altered in 15% of the myeloid tumors. Meis1 encodes a novel homeobox protein and its homeodomain is related to the homeodomain of PBX1. Recent work focuses on the characterization of Meis1. This group has identified the DNA sequence that is bound by Meis1. They have recently determined that Meis1 is capable of cooperating with the AbdB class of Hox proteins, distinguishing it from the PBX proteins. Sequence comparison reveals that Meis1 is well conserved through evolution; the entire protein is > 90 % identical between Xenopus and mouse. This degree of conservation suggests that Meis1 plays an important role in development, and our goal is to determine the role Meis1 plays in development and leukemia. In another model system, Dr. Buchberg is investigating the influence of genetic modifier loci on the incidence of polyp development in colon cancer in collaboration with the laboratory of Dr. Linda Siracusa. Mutations in the adenomatous polyposi coli (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. This group has identified a candidate gene for Mom1. The gene for secretory type II Phospholipase A2 (Pla2s) maps to the same region that contains Mom1, and displays 100% concordance between allele type and tumor susceptibility. Expression analysis revealed that Mom1 susceptible strains are null for Pla2s activity. Results indicate that Pla2s acts as a novel gene which modifies polyp number by altering the cellular microenvironment within the intestinal crypt. They are in the process of determining the mechanism by which Pla2s acts to confer resistance to polyp formation as well as to determine the role of Pla2s in the development of human colon cancer. In addition, they are designing strategies to identify additional modifier loci involved in cancer susceptibility. Keywords: myeloid leukemia, Meis1, cancer susceptibility, Mom1, mouse models of disease | ||||
| Selected Publications Montgomery, J.C., Silverman, K. and Buchberg, A.M.: Mouse Chromosome 11. Mammalian Genome 7: S190-S208, 1997. Steelman, S. Moskow, J.J., Muzynski, K., North, C., Druck, T., Montgomery, J.C., Huebner, K., Daar, I.O. and Buchberg, A.M.: Identification of a conserved family of Meis1-related homeobox genes. Gen. Res. 7: 142-156, 1997. Kurooka, H., Kato, K., Minoguchi, S., Takahashi, Y., Ikeda, J., Habu, S., Osawa, N., Buchberg, A.M., Moriwaki, K., Shisa, H. and Honjo, T. : Cloning and characterization of the nucleoredoxin gene that encodes a novel nuclear protein related to thioredoxin. Genomics 39: 331-339, 1997. Narducci, M.G., Virgilio, L., Engiles, J.B., Buchberg, A.M., Billips, L., Facchiano, A., Croce, C.M., Russo, G. and Rothstein, J.L.: The murine Tcl1 oncogene: Embryonic and lymphoid cell expression. Oncogene 15: 919-926, 1997. Shen, W.-F., Montgomery, J.C., Rozenfeld, S., Moskow, J.J., Lawrence, H.J., Buchberg, A.M. and Largman, C.: The Abd-B-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol. Cell Biol. 17: 8448-6458, 1997. Swift GH, Liu Y, Rose SD, Bischof LJ, Steelman S, Buchberg AM, Wright CV, MacDonald RJ: An endocrine-exocrine switch in the activity of the pancreatic homeodomain protein PDX1 through formation of a trimeric complex with PBX1b and MRG1(MEIS2). Mol Cell Biol. 1998 Sep;18(9):5109-20. Pekarsky Y, Druck T, Cotticelli MG, Ohta M, Shou J, Mendrola J, Montgomery JC, Buchberg AM, Siracusa LD, Manenti G, Fong LY, Dragani TA, Pekarsky Y, Campiglio M, Siprashvili Z, Druck T, Sedkov Y, Tillib S, Draganescu A, Wermuth P, Rothman JH, Huebner K, Buchberg AM, Mazo A, Montgomery JC, Silverman KA, Buchberg AM: Encyclopedia of the mouse genome VII. Mouse chromosome 11. Mamm Genome. 1998;8. Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G: Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J. 1998 Jul 1;17(13):3714-25. Bischof LJ, Kagawa N, Moskow JJ, Takahashi Y, Iwamatsu A, Buchberg AM, Waterman MR: Members of the meis1 and pbx homeodomain protein families cooperatively bind a cAMP-responsive sequence (CRS1) from bovine CYP17. J Biol Chem. 1998 Apr 3;273(14):7941-8. Lawrence, H.J., Rozenfeld, S., Cruz, C., Matsukuma, K., Kwong, A., Komuves, L., Buchberg, A.M. and Largman, C.: Leukemia, in press. | ||||
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