Section: Research

Postdoctoral Position Available

Michelle Kelliher, Ph.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cancer Biology
   Molecular Genetics and Microbiology

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Apoptosis and cancer

Mouse models of leukemia

Aberrant expression of developmentally important regulatory genes has been increasingly implicated among hematopoietic malignancies. Abnormalities in either abundance or activity of these gene products can result in inappropriate expression of genes critical to the processes of cell growth and differentiation. I have been studying the basic domain helix-loop-helix (bHLH) family of transcription factors including TAL1, TAL2, LYL1 and E2A, all of which are associated with human leukemia. The overall goal of my research is to assess how these bHLH proteins contribute to disease development using the mouse as a model system.

Most cases of pediatric T cell acute lymphoblastic leukemia (T-ALL) involve tumor specific activation of the bHLH gene TAL1/SCL. Ectopic expression of tal1 in the thymus of mice results in the development of clonal T cell leukemia/lymphoma. The TAL-1 protein, normally expressed in hematopoietic progenitors and erythroid cells, binds DNA once bound to E proteins (e.g. E47 and HEB), critical bHLH transcription factors which regulate lymphoid development. Stable tal1/E47 heterodimers are detected in mouse leukemic cells, suggesting that tal1 may contribute to leukemia by interfering with E protein function(s). Consistent with this idea, E2A-deficient mice and mice expressing a DNA binding mutant of tal-1 develop disease (O'Neil et al., 2001). A specific focus of our research is to ask whether tal1 transforms by interfering with E protein function(s) and to identify E47/HEB target genes de-regulated by tal1 expression. An additional objective is to identify genes that collaborate with tal1 to induce leukemogenesis, using retroviral insertional mutagenesis.  We have identified retroviral insertions in notch 1, myc and ikaros loci and are currently testing whether expression of these genes accelerates tal1-induced leukemogenesis.

The E2A locus is also the target of two chromosomal translocations associated with human leukemia. The    t(17;19) translocation generates the chimeric fusion protein E2A-HLF which contains the transactivation domains of E2A and the bZIP domain of hepatic leukemia factor (HLF). To mimic the human translocation and to create a mouse model of E2A-HLF-induced leukemogenesis, we have generated an E2A-HLF "knock-in" mouse. Mice homozygous for E2A-HLF exhibit defects in  B cell development, consistent with studies of E2A-deficient mice.  To determine if E2A-HLF expression predisposes mice to the development of leukemia we are performing chemical mutagenesis.

The death domain kinase Rip1 in TNF and Toll receptor signaling

Another area of research in my laboratory involves study of apoptosis or programmed cell death and how deregulation of this process contributes to the development of malignancy. We are studying a death domain kinase Rip1 which participates in TNF signaling. To define the contribution of Rip1 to TNF signaling, we adopted a genetic approach and created rip1-deficient mice. Murine embryonic fibroblasts that lack rip are highly sensitive to TNF-induced cell death due to an impaired NF-kB response (Kelliher et al., 1998). However, the introduction of a kinase defective allele of rip1 into rip-/- cells rescues the NF-kB defect, suggesting that the kinase activity of rip is not required for TNF-induced NF-kB activation. To elucidate the role of the kinase activity of rip1, we are identifying rip1 kinase substrates and have generated embryonic stem (ES)cells that express only kinase inactive Rip1. 

Recent work in the lab has also implicated Rip1 in Toll receptor 3 induced NF-kB activation.  Rip1 deficient cells fail to activate NF-kB or induce cytokine production when stimulated with double stranded RNA such as poly IC.  Rip1 does not mediate IRF3 activation but activates NF-kB by associating with the Trif adapter protein.  Current studies in the lab are focused on whether Rip1 also mediates MAPK activation or apoptosis in response to TLR3 activation.

Office: LRB-421
Phone: 508-856-8620
E-mail: Michelle.Kelliher@umassmed.edu
Keywords: Genetic Systems, Cancer Biology, Signal Transduction

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Kelliher for additional details.