Michael J. Thirman, M.D.

Characterization of 11q23 translocations in acute myeloid and acute lymphoblastic leukemia

Research Summary

The research in my laboratory focuses on the characterization of 11q23 translocations, frequent chromosomal aberrations in both acute myeloid and acute lymphoblastic leukemia. We have found that the critical consequence of these 11q23 chromosomal breaks is the disruption of the MLL gene and its subsequent in-frame fusion to a gene on other chromosomes. In previous work, we developed a molecular diagnostic technique for identifying MLL gene rearrangements in all patients with 11q23 translocations. Subsequently, we cloned the gene, ELL, that fuses to MLL in the (11;19)(q23;p13.1) translocation. Recently, we have characterized the spatial and temporal pattern of expression of ELL in murine development. By immunofluorescence, we have determined that ELL is expressed diffusely in the nucleus but excludes nucleoli. Recently, ELL was found to function as an RNA Polymerase II transcription elongation factor. The elucidation of the aberrant functions of ELL when fused to MLL is our major area of investigation at this time. Experiments in progress in the laboratory include identification of proteins that interact with MLL and ELL, development of a mouse model of MLL-ELL leukemia, cloning of (11;19) chromosomal breakpoint junctions, and characterization of potential targets of transcriptional elongation by ELL.

Selected Papers

Lavau C, Luo RT, Du C and Thirman MJ. (2000). Retrovirus medoated gene transfer of MLL-ELL transforms primary myeloid progenitors and causes acute myeloid leukemias in mice. Proceedings of the National Academy of Sciences USA, 97:10984-10989.

Somone F, Polak PE, Luo RT, Kaberlein JJ, Levitan DA and Thirman MJ. (2001). EAF1, a novel ELL associated factor that is delocalized by expression of the MLL-ELL fusion protein. Blood, 98:201-209

Luo RT, Lavau C, Du C, Simone F, Polak PE, Kawamata S and Thirman MJ. (2001). The elongation domain of ELL is dispensable but its EAF1 interaction domain is essential for MLL-ELL induced leukemogenesis. Molecular and Cellular Biology, 21:5678-5687.

Simone F, Luo RT, Polak PE, Kaberlein JJ and Thirman MJ. (2003). ELL-Associated Factor 2(EAF2), a functional homolog of EAF1 with alternative ELL binding properties. Blood, 101:2355-2362.

Polak PE, Simone F, Kaberlein JJ, Luo RT and Thirman MJ. (2003). ELL and EAF1 are Cajal body components that are disrupted in MLL-ELL leukemia. Molecular Biology of the Cell 14:1517-1528.