Michelle Le Beau, Ph.D.

Molecular Analysis of Recurring Chromosomal Abnormalities in Human Tumors; Identification of Cooperating Mutations and Genetic Pathways Leading to Transformation

Research Summary

Human tumors are characterized by recurring chromosomal abnormalities. During the past decade, the genes that are located at the breakpoints of a number of recurring chromosomal abnormalities in human tumors have been identified. Molecular analysis has revealed, that alterations in the level of expression of these genes, or in the properties of the encoded proteins resulting from the chromosomal rearrangement, play an integral role in the process of malignant transformation. Dr. Le Beau has had a long-standing interest in identifying the recurring chromosomal abnormalities in human tumors, and correlating specific chromosomal abnormalities with morphological and clinical features of the neoplastic disease, such as response to therapy and survival.

Ongoing projects include:

1) Molecular cloning of a myeloid leukemia-related gene involved in the 5/del(5q) characteristic of the major subtype of therapy-related acute myeloid leukemia (alkylating-agent induced).

2) Genetic characterization of murine models for acute myeloid leukemia (RUNX1/ETO, PML-RARA, BXH2, NF1+/-, K-RAS), and identification of secondary, cooperating mutations and genetic pathways to leukemogenesis. Application of murine models for pre-clinical drug testing.

3) Elucidation of the mechanism for the genetic instability characteristic of chromosomal fragile sites (loci which are prone to undergo breakage and rearrangement). These studies involve the analysis of DNA replication and cell cycle checkpoints in fragile site instability, as well as the role of DNA repair pathways in mediating repair of damage at fragile sites.

Selected Papers

Lucas I, Palakodeti A, Jiang Y, Young DJ, Jiang N, Fernald AA, Le Beau MM.  High throughput mapping of origins of replication in human cells. EMBO Rep 8:770-777, 2007.

Joslin JM, Fernald AA, Tennant TR, Davis EM, Kogan SC, Anastasi J, Crispino JD, Le Beau MM.  Haploinsufficiency of EGR1, a candidate gene in the del(5q), leads to the development of myeloid disorders.  Blood 110:719-726, 2007.

Qian Z, Chen L, Fernald AA, Williams BO, Le Beau MM. A critical role for Apc in hematopoietic stem and progenitor cell survival. J Exp Med 205:2163-75, 2008.

Shannon KM, Le Beau MM. Cancer: hay in a haystack.  Nature 451:252-253, 2008.

Jiang Y, Lucas I, Young DJ, Davis EM, Karrison T, Rest JS, Le Beau MM. Common fragile sites are characterized by histone hypoacetylation.  Hum Mol Genet 18:4501-4512, 2009.   
 
Wang J, Fernald AA, Anastasi J, Le Beau MM, Qian Z. Haploinsufficiency of Apc leads to ineffective hematopoiesis. Blood 115:3481-3488, 2010.

Palakodeti A, Lucas I, Jiang Y, Young DJ, Fernald AA, Karrison T, Le Beau MM.  Impaired replication dynamics at the FRA3B common fragile site.  Hum Mol Genet 19:99-110, 2010. 

Stoddart A, Tennant TR, Fernald AA, Anastasi J, Brodsky FM, Le Beau MM. The clathrin-binding domain of CALM-AF10 alters the phenotype of myeloid neoplasms in mice.  Oncogene. 2011 Jun 27. doi: 10.1038/onc.2011.251.
 
Odenike O, Le Beau MM.  The dawn of the molecular era of the myelodysplastic syndromes.   N Engl J Med 364:2545-6, 2011.