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

Le Beau MM, Rassool FV, Neilly ME, Espinosa III R, Glover TW, Smith DI, McKeithan TW. (1998). Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: implications for the mechanism of fragile site induction. Human Molecular Genetics 7:755-761.

Lai F, Godley LA, Fernald AA, Espinosa III R, Zhao N, Pamintuan L, Till BG, Le Beau MM. (2001). Transcript map and comparative analysis of the 1.5 Mb commonly deleted segment of human 5q31 in malignant myeloid diseases with del(5q). Genomics 71:235-245.

Le Beau MM, Bitts S, Davis EM, Kogan SC.  (2002). Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic leukemia. Blood 99:2985-2991.

Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM, Crispino J. (2002). Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down Syndrome. Nature Genet. 32:148-152.

Qian Z, Fernald AA, Godley LA, Larson RA, Le Beau MM. (2002). Expression profiling of CD34+ hematopoietic stem/progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Proc. Natl. Acad. Sci. USA 99:14925-14930.