Richard Van Etten, MD, PhD Principal Investigator Richard Van Etten BS, Mathematics, M.I.T., Cambridge, MA BS, Biology, M.I.T., Cambridge, MA MD, Stanford University School of Medicine, Stanford, CA PhD, Biophysics, Stanford University, Stanford, CA Dr. Van Etten received an MD and PhD in Biophysics from Stanford University School of Medicine, where he worked with David Clayton on molecular genetics of mammalian mitochondrial DNA. After postgraduate training in internal medicine and hematology at Brigham & Women's Hospital in Boston, he was a postdoctoral fellow with David Baltimore at the Whitehead Institute. He was a faculty member in the Departments of Genetics and Medicine at Harvard Medical School until 2003, when he joined MORI as Professor of Medicine and Director of Hematologic Malignancies. The Van Etten lab studies the molecular pathogenesis of leukemia with an emphasis on dysregulated tyrosine kinases and mouse model systems. A new area of interest is oxidative stress and the role of the peroxiredoxin family of antioxidant enzymes in cell signaling and cancer.

Wayne W. Chan, BSE MD/PhD Student in Cell and Molecular Physiology Wayne Chan BSE, Chemical Engineering, Princeton University, NJ My work is focused on defining the signaling pathways downstream of Bcr-Abl in the molecular pathogenesis of chronic myelogenous leukemia (CML). Our laboratory has shown that binding of the adaptor protein Grb2 at Tyr177 of the Bcr-Abl fusion protein is required for the induction of a CML-like myeloproliferative disease. However, these results do not exclude the binding of other SH2 domain containing proteins at Tyr177. In order to dissect the roles of other adaptor proteins in the pathogenesis of CML, we have taken a genetic approach and generated various Bcr-Abl mutants with different predicted binding specificities. I am currently testing these mutants to determine if they confer a different phenotype in our bone marrow transplant mouse model.

L. Cristina Gavrilescu, PhD Postdoctoral Fellow L. Cristina Gavrilescu Maitrise, Cellular Biology and Physiology, University Pierre and Marie Curie, Paris, France MS, Biology, New York University, New York, NY PhD, Immunology, Cornell University, Ithaca, NY My work is focused on defining the signaling pathways involved in 8p11 myeloproliferative syndrome (EMS), a recently characterized new form of chronic myeloid leukemia (CML). EMS is due to an (8;13) translocation, resulting in the fusion of the N-terminal part of ZNF198, a nuclear protein, and most of the intracellular domain of the fibroblast growth factor receptor 1 (FGFR1). The expressed fusion protein ZNF198-FGFR1 homodimerizes in the cytoplasm and induces a constitutive activation of the FGFR1 tyrosine kinase domain. By finding which specific pathways are activated in ZNF198-FGFR1 transfected Ba/F3 and NIH 3T3 cells, we can define the critical molecular mechanisms of induction of EMS-like disease. Our laboratory developed a bone marrow transplant mouse model of ZNF198-FGFR1-induced leukemia/lymphoma, and I am using it to test these pathways in primary leukemia cells. I will then carry out a preclinical testing of molecularly targeted therapeutic agents for the 8p11 syndrome in these mice.

Mo-Ying Hsieh Graduate Student Mo-Ying Hsieh

Nilamani Jena, PhD Postdoctoral Fellow Nilamani Jena BS, Orissa University of Agriculture and Technology, Bhubaneswar, India MS, Madurai Kamaraj University, Madurai, India PhD, Kimmel Cancer Center Thomas Jefferson, University, Philadelphia, PA Deregulated cell proliferation or reduced cell death or both are inalienable components of tumor development. The BCR-ABL oncogene, which causes chronic myeloid leukemia, induces cellular proliferation and inhibits apoptosis. BCR-ABL activates several pathways leading to activation of the cell cycle machinery. The process of cell cycle is quite complex, and this complexity is amplified due to presence of redundancy in enzymes and their regulators. The objective of my research is to identify and characterize specific cell cycle modulators that are targets of BCR-ABL mediated cell proliferation signals. Previously, I have shown that, despite the redundancy in D-type Cyclins, Cyclin D2 is essential for BCR-ABL induced cell proliferation. At present, my goal is to identify the role of cyclin dependent kinase inhibitor p21 in BCR-ABL mediated cell proliferation.

Katherine Lazarides, BS Research Assistant Katherine Lazarides BS, University of Massachusetts, Amherst

Yi-Fen Lu, PhD Graduate Student Yi-Fen Lu MS Immunology, National Taiwan University, Taiwan PhD Candidate, Sackler School, Tufts University, Boston My work is mainly focused on developing potential immunotherapy of relapse-phase CML. Despite the clinical success of treating patients with imatinib, the Abl kinase inhibitor is never curing. Allogeneic stem cell transplantation (allo-SCT) thus remains the only curative therapy. For patients having CML relapse after allo-SCT, donor leukocyte infusion (DLI) could induce remission in most of the patients; however, the mechanism is not fully understood. One part of my work seeks to understand the mechanism underlying this phenomenon. I am also developing the therapeutic mouse model that combines the use of imatinib and DLI on mixed chimera.

Christophe Walz, MD Postdoctoral Fellow Christophe Walz

Rinat Yacobi, PhD Postdoctoral Fellow Rinat Yacobi BS, Ben-Gurion University, Be'er Sheva, Israel MS, Sackler Faculty of Medicine, Tel-Aviv University, Israel PhD, Sackler Faculty of Medicine, Tel-Aviv University, Israel Fusion of c-Abl to Bcr results in a constitutively active tyrosine kinase that is the direct cause of the Philadelphia chromosome-positive leukemias. A better understanding of the mechanisms of regulation of c-Abl and Bcr-Abl tyrosine kinase activity is necessary to improve upon therapies such as imatinib mesylate that target this activity. We have recently demonstrated that Bcr-Abl, which lacks an N-terminal myristoyl group, is autoinhibited through its SH3 domain. This and other biochemical and genetic evidence suggests that Abl kinases are regulated in part through intramolecular effects and in part through cellular inhibitors acting in trans. I am testing this hypothesis by assaying the catalytic activity of a series of mutants of c-Abl and Bcr-Abl to determine the role of trans inhibitors and of tyrosine phosphorylation in Abl regulation. These studies should illuminate the mechanism of regulation of Abl and provide information essential to the design of the next generation of kinase inhibitor drugs.

Virginia Zaleskas, MD Postdoctoral Fellow Virginia Zaleskas MD, Tufts University School of Medicine Our laboratory and others have demonstrated activation of the JAK/STAT signaling pathway by Bcr-Abl, the product of the Philadelphia chromosome in chronic myeloid leukemia (CML). However, the importance of this pathway to the pathogenesis of CML and its utility as a therapeutic target in treatment of CML are not known. My project focuses on the mechanism of activation of STAT proteins in CML cells and the role of this pathway in leukemogenesis by Bcr-Abl.