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.

Figures

Models of transformation by the tal-1/scl oncogene. The inhibition model psotulates that ectopic expression of tal-1 in the thymus disrupts E47/HEB transcription of genes critical for thymocyte differentiation. The transactivation model suggests that novel oncogenes are induced by tal-1/E47 heterodimer. Both models may contribute to tal-1/scl leukemogenesis.

Recent Publications:

Kelliher MA, Seldin DC, Leder P (1996). Tal-1 induces T cell acute lymphoblastic leukemia accelerated by casein kinase IIa. EMBO J., 5 (19): 5160-5166.

Kelliher MA, Grimm S, Ishida Y, Kuo F, Leder P. (1998). The death domain kinase RIP mediates the TNF-a induced NF-kB signal. Immunity, 8: 297-303.

Devin A, Cook A, Lin Y, Rodriguez Y, Kelliher M, Liu Z. (2000). The distinct roles of TRAF2 and RIP in TNFR1-mediated IKK activation: IKK is recruited into the TNFR1 complex via TRAF2 while its activation is mediated by RIP. Immunity 12, 419-429.

Lin Y, Devin A, Cook A, Keane M, Kelliher M, Lipkowitz S, Liu Z. (2000). The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkB kinase and c-jun N-terminal kinase. Mol. and Cell. Biol. 20: 6638-6645.

O’Neil J, Billa M, Oikemus S, Kelliher MA. (2001). The DNA binding activity of TAL-1 is not required to induce leukemia/lymphoma in mice. Oncogene 20, 3897-3905.

Cusson N, Oikemus S, Kilpatrick ED, Cunningham L, Kelliher M. (2002). The death domain kinase RIP protects thymocytes from tumor necrosis factor receptor type 2-induced cell death.  J Exp Med. 196:15-26.

O'Neil J, Ventura JJ, Cusson N, Kelliher M.  (2003).  NF-kappaB activation in premalignant mouse tal1/scl thymocytes and tumors.  Blood 102(7):2593-6.

Lee TH, Huang Q, Oikemus S, Shank J, Ventura JJ, Cusson N, Vaillancourt RR, Su B, Davis RJ, Kelliher MA. (2003).  The death domain kinase RIP1 is essential for tumor necrosis factor alpha signaling to p38 mitogen-activated protein kinase.  Mol Cell Biol. 23:8377-85. 

Meylan E, Burns K, Hofmann K, Blancheteau V, Martinon F, Kelliher M., Tschopp J. (2004).  RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.  Nat Immunol.5(5):503-7.

O'Neil J, Shank J, Cusson N, Murre C, Kelliher M. (2004). Tal1/scl induces leukemia by inhibiting the transcriptional activity of E47/HEB.  Cancer Cell (in press).

Lee TH, Shank J, Cusson N, Kelliher M.  (2004).  The kinase activity of Rip1 is not required for TNF-a-induced Ikk or p38 MAP kinase activation or for the ubiquitination of Rip1 by Traf 2.  J.Biol.Chem. (in press).

Vivarelli M, McDonald D, Miller M, Cusson N, Kelliher M, Geha RS. (2004).  Rip 1 links TLR4 to Akt and is essential for cell survival in response to LPS stimulation.  J. Exp Med.  200:399-404.

Das S, Cho J, Lambertz I, Kelliher MA, Eliopoulos AG, Du K, Tsichlis P. (2005).  Tpl2/Cot signals activate ERK, JNK and NF-kB in a cell-type and stimulus-specific manner.  J. Biol. Chem 280:23748-23757.

Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA. (2005).  Rip1 mediates the Trif-dependent Toll-like receptor 3 and 4-induced NF-kB activation but does not contribute to IRF-3 activation.  J. Biol. Chem.  280: 36560-6.

O,Neil J, Calvo J, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH, Alt FW, *Kelliher M,  *Look AT.  (2006).  Activating Notch1 mutations in mouse models of T-ALL.  Blood 107:781-5.  (*senior co-authors).

Shank-Calvo J, Draheim K, Bhasin M,  Kelliher MA.  (2006).  p16Ink4a or p19Arf loss contributes to Tal1-induced leukemogenesis in mice. Oncogene, 25:3023-31.

Chang PY, Draheim K, Kelliher MA, Miyamoto S.  (2006).  NFKB1 is a direct target of the TAL1 oncoprotein in human T leukemia cells.  Cancer Research, 66:6008-13.

Sharma VM*, Calvo JA*, Draheim K, Cunningham L, Hermance N, Beverly L, Krishnamoorthy V, Bhasin M, Capobianco A, Kelliher MA.  (2006).  Notch1 contributes to mouse T cell leukemia by directly inducing the expression of c-myc.  Mol. Cell. Biol. [E ahead of print 5 Sept. 2006] (* equal contribution).

Potential Rotation Projects

Mechanism(s) of Leukemogenesis

Project 1: We have used retroviral insertional mutagenesis to identify genes that collaborate with the basic helix-loop-helix b(HLH) tal-1/scl oncogene. Using genomic DNA from retrovirally-infected tumors, you will use inverse PCR to isolate and identify the collaborating oncogenes.

Project 2: Using IPCR, we have identified the notch 1 locus as a frequent site for retroviral integration in Mo-MLV-infected tal-1/scl transgenic mice. To test whether expression of an activated notch1 allele accelerates tal-1/scl-induced leukemogenesis, you will reconstitute mice with wt or tal-1/scl hematopoietic precursors infected with a control or an activated notch1 retrovirus. The effects of notch and tal-1/scl expression on thymocyte development will be examined. If disease acceleration is observed, tumor cell lines will be established from mice to examine how notch1 and tal-1/scl proteins collaborate to induce disease in mice.

TNF signaling in mouse development and cancer

Project 1: Using Affymetrix oligonucleotide arrays, we have identified a number of novel, TNF-responsive genes. To determine the contribution of these genes to mouse development and TNF signaling, we have used gene targeting in embryonic stem cells to generate mice deficient for one of these genes. Sensitivity to TNF-induced cell death as well as IKK, jnk and p38 MAP kinase activation in response to TNF needs to be examined in murine embryonic fibroblasts derived from this mouse.

Project 2: The death domain kinase RIP1 mediates the NF-kB repsonse to TNF, yet the kinase activity of RIP1 does not appear required. These studies suggest RIP1 may mediate IKK activation by recruiting another as yet unidentified kinase. Using biochemical approaches, you will isolate and identify proteins that interact with RIP1.

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.