Richard Van Etten, MD, PhD Principal Investigator Phone: 617-636-6449 Fax: 617-636-6127 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 617-636-6424 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.

Alex Danilov Hematology/Oncology Fellow Alex Danilov             Darci Gaiotti Clinical Fellow 617-636-6421 Darci Gaiotti           L. Cristina Gavrilescu, PhD Postdoctoral Fellow 617-636-6425 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 While CML is due to the Bcr-Abl translocation, many other human CML-like diseases have been identified in the last decade, and are induced by other translocations, in particular those involving the intracellular part of type II RTKs (Receptor Tyrosine kinases). I am particularly focusing on FGFR1 and its different fusion partners (ZNF198, FOP, etc) and PDGFRa and it’s fusion partners (Fip1L1, Bcr). These diseases take then the name of EMS (8p11 myeloproliferative syndrome) in cases involving the intracellular domain of FGFR1, or CEL (chronic eosinophilic leukemia) if the platelet-derived growth factor receptor alpha subunit (PDGFRa) is involved. I Myc-tagged a variety of ZNF1980FGFR1 point mutants for ease of study, reconstructed the patient-isolated Bcr-PDGFRa oncogene and created specific point-mutants, and am working on creating a lentiviral vector that would express at the same time both an siRNA and the oncogene of interest. Our laboratory developed a bone marrow transplant mouse model for leukemia/lymphoma, using retroviruses encoding the oncogenes of interest, that I am using it to carry out a preclinical testing of molecularly targeted therapeutic agents for the different growth-factor-receptor-derived oncogenes I study.

Mo-Ying Hsieh Graduate Student 617-636-9539 Mo-Ying Hsieh

Nilamani Jena, PhD Postdoctoral Fellow 617-636-3098 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 617-636-0148 Katherine Lazarides BS, University of Massachusetts, Amherst

Juliana Lewis Graduate Student 617-636-0148 Juliana Lewis           Yi-Fen Lu, PhD Graduate Student 617-636-0148 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.

Marcos Salazar Graduate Student 617-636-1107 Marcos Salazar         Christoph Walz, MD Postdoctoral Fellow 617-636-6424 Christoph Walz MD, University of Heidelberg Chronic myeloproliferative disorders (CMPD) are clonal disorders of the myeloid stem cell. In a subset of patients with CMPD, acquired aberrations of certain protein molecules, so-called tyrosine kinases as ABL1 and JAK2, can be frequently identified. Using bone marrow transplantation models, we are trying to determine the impact of ABL1 and JAK2 downstream molecules for the molecular pathogenesis, in particular the role of Signal Transducers and Activators of Transcription (STAT5) proteins. In addition, we are investigating if and how JAK2 expression levels may alter the myeloproliferative disease phenotype in vivo.

Virginia Zaleskas, MD Postdoctoral Fellow 617-636-1108 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.