Our laboratory is focused on the elucidation of fundamental mechanisms of cell growth, survival and senescence during normal and neoplastic development with the overall goal of identifying novel pathways for therapeutic targeting of leukemia and solid tumors. The areas of current interest include:
1) Epigenetic Mechanisms during Development, Cancer Pathogenesis and Senescence: We are investigating basic mechanisms regulating chromatin structure and DNA methylation using biochemical, genetic and knockout murine and zebra fish models. Our laboratory has cloned a novel chromatin remodeling helicase, named PASG, which is involved in genomic methylation critical for regulating the senescence. We are currently investigating the mechanisms by which PASG affects chromatin structure leading to genomic instability and replicative senescence as well as developing models for therapeutic targeting of senescence pathways.
2) Activating Mutations of the c-KIT Tyrosine Kinase in Leukemia: The role of cytokines and their cognate receptors during normal and neoplastic cell growth, differentiation and programmed cell death. Current work is focused on defining the signal transduction pathways resulting from activating mutations of the c-KIT tyrosine kinase receptor and identifying therapies to block the survival and drug resistant mechanisms in leukemias and solid tumor expressing mutant forms of the receptor.
3) Cancer Predisposition Syndromes: Children with inherited bone marrow failure syndromes usually have characteristic physical abnormalities as well as a predisposition to develop both leukemia and solid tumors. We are focused on the identification of a causative gene in one of these syndromes based on the observation of a patient with an inherited chromosome deletion. The identification and functional analysis of this pathway will help us understand mechanisms of bone marrow failure as well as cancer predisposition.
4) Immunotargeted Therapies for Hematologic Malignancies: This area of research involves the translation of targeted immunotherapies for patients with cancer. Studies are directed toward the development of human monoclonal antibody targeting of tumor cells as well as the use of vaccines to generate anti-tumor responses. We have developed a human monoclonal antibody directed against the CD1a protein, which is expressed on a subset of thymocytes and Langerhans cells. Experimental studies are investigating this antibody in terms of diagnostic scanning, therapeutic targeting, Graft-vs-Host Disease prevention and the augmentation of cancer vaccine efficacy.
- Arceci RJ, Sande J, Lange B, Shannon K, Franklin J, Hutchinson R, Vik T, Flowers D, Leopold L, Sherman ML, Smith FO, Bernstein I, Sievers EL. Safety and Efficacy of Gemtuzumab Ozagamicin (Mylotarg) in Pediatric Patients with Advanced CD33-Positive Acute Myeloid Leukemia. Blood, (In Press)
- Sun L, Arceci RJ. Altered Epigenetic Patterning Leading to Replicative Senescence and Reduced Longevity: A Role of a Novel SNF2 Factor, PASG. Cell Cycle. 4(1); 2005.
- Sun, L-Q., Lee, D.W., Xiao, W., Raabe, E.H., Miao, D., Huso, D.L. and Arceci, R.J., Growth Retardation and Premature Aging in Mice with Disruption of the SNF2-like Gene, PASG, Genes and Development, 18: 1035-1046; 2004.