ASH News Daily - Saturday, December 10, 2011 - (Page A-2)

Page A–2 ® ASH News Daily 2011 Editorial Board Editor Joseph Mikhael, MD, MEd Mayo Clinic Arizona Authors Michael R. Bishop, MD Medical College of Wisconsin Amanda M. Brandow, DO, MS Medical College of Wisconsin David Garcia, MD University of New Mexico Cancer Center Shari A. Ghanny, MD McMaster University Heather Landau, MD Memorial Sloan-Kettering Cancer Center Julie A. Panepinto, MD, MSPH Medical College of Wisconsin Barbara Pro, MD Fox Chase Cancer Center ALL Notch: A True Chameleon T By heather landau, Md he role of Notch in human cancer was originally suggested through identification of a chromosomal translocation involving the human NOTCH1 gene found in a patient with T-cell acute lymphocytic leukemia (T-ALL). Since that discovery, aberrant Notch signaling has been found to be involved in a wide variety of human neoplasms, yet a uniform model for the role of notch signaling in tumorigenesis remains elusive. Indeed, Notch may act as an oncogene, a tumor suppressor, or even as an exquisitely selective immune regulator. Thus, Notch genes change their colors depending on the cellular context. During this morning’s Scientific Michael A. Rosenzweig, MD City of Hope The information contained in ASH News Daily is provided solely for educational purposes. A diversity of opinions exists in the field of hematology, and the articles in this publication are often intended to inform readers about more than one point of view. These articles are not comprehensive and should not be used as a substitute for traditional sources of hematology information, traditional diagnostic and treatment information, or the individual judgment of health-care providers. The views expressed in ASH News Daily do not necessarily represent ASH’s views, and their inclusion in this publication should not be interpreted as an endorsement by ASH. ASH is not responsible for any inaccurate or inappropriate use of the information, publications, products, or services discussed or advertised within. ©2011 by the American Society of Hematology All materials contained in this newspaper are protected by copyright laws and may not be used, reproduced, or otherwise exploited in any manner without the express prior permission of ASH News Daily. Contributing authors have declared any financial interest in a product or in potentially competing products, regardless of the dollar amount. Any such financial interest is noted with the author byline. Program session, “Role of Notch Signaling in Normal and Malignant Hematopoiesis,” Dr. Iannis Aifantis, New York University School of Medicine, will show that inactivation of the Notch pathway is associated with a subset of patients with chronic myelomonocytic leukemia (CMML). Furthermore, defective Notch signaling in mouse hematopoietic stem cells leads to mice with monocytosis, leukocytosis, and large spleens, a phenotype consistent with CMML. But how can the Notch signaling be tumorpromoting and tumor-suppressing in the same tissues? Does Notch really change colors? Dr. Aifantis will show that while the Notch pathway does not change, the derepression of the negative transcriptional regulator, Hairy, and enhancer of split 1 (HES1) leads to myeloproliferation. Why evolutionary biology allows a hairy enhancer to run wild may be explained by a novel role of Notch signaling during early hematopoiesis that has been discovered by Dr. Aifantis and colleagues. This session will take place in Room 6DE of the San Diego Convention Center at 7:30 a.m. and again tomorrow at 9:30 a.m. If Notch appears red when oncogenic and white like an innocent bystander when tumor-suppressing, its role in graft-versus-host disease (GVHD) should be colored yellow akin to sunlight — a symbol of optimism. While allogeneic stem cell transplantation (SCT) itself has extended lives of many patients with hematologic malignancies and other disorders, GVHD remains a dreaded consequence with limited management strategies. Dr. Ivan Maillard and colleagues at the Center for Stem Cell Biology in Ann Arbor will provide new hope when they show that Notch-deficient T cells reduce GVHD severity and lethality but maintain their beneficial graft-versus-tumor (GVT) activity. The mechanisms that underlie these observations are actively being investigated and may reveal targets for pharmacologic manipulation of notch signaling peri or post SCT. Dr. Anna Bigas, Institut Municipal d’Investigacio Mèdica, Barcelona, will review the role of Notch signaling in the generation of hematopoietic stem cells in the embryo. She will share new discoveries on how Notch regulates this process; this includes the complex interplay between the GATA2 gene and HES1. It is Dr. Bigas’ opinion that this research “will ASH NEWS DAILY Saturday, December 10, 2011 help to understand mechanisms controlled by Notch that may be relevant in stem cell biology and leukemia.” Since mutations in this pathway are being found not only in T-ALL, but also in many different oncologic malignancies (B-CLL or solid tumors), the implications of her research may even be more broadly realized. Like a chameleon, Notch chang- es colors. What accounts for these pleotropic effects that are governed by Notch signaling? Is it that four Notch proteins have distinct activities and outcomes? At this year’s meeting, take note of the wealth of studies detailing how Notch may be important in chronic lymphocytic leukemia (CLL) (abstract #283: 7:00 a.m., Monday, December 12), mantle cell lymphoma (abstract #436: 11:15 a.m., Monday, December 12), and multiple myeloma (abstract #1111: 5:30-7:30 p.m., today). It is intriguing to speculate that in the future we may understand how to effectively target the Notch pathway to treat these disorders; however, it is likely that a colorful palette of strategies will be required. Dr. Landau indicated no relevant conflicts of interest. Dr. Brandon McMahon, Northwestern University, Chicago, presents during the ABIM MOC Learning Session. Watch the Live Broadcast of the Nobel Prize Award Ceremony Grab your coffee and pastry and head to Room 3 (SDCC, Upper Level) to watch the live broadcast of the Nobel Prize Award Ceremony at 7:30 this morning. ASH member Ralph M. Steinman, MD, of Rockefeller University in New York was awarded the Nobel Prize in Physiology or Medicine for his pioneering discovery of dendritic cells and their role as critical antigen presenting cells of the immune sys- tem. Unfortunately, Dr. Steinman never knew of this great honor; he died after a four-year battle with pancreatic cancer unbeknownst to the prize committee on Friday, September, 30, just days before the announcement. Dr. Steinman shared the award with two other physician scientists, Bruce Beutler, from University of Texas Southwestern Medical Center and Scripps Research Center, and Jules Hoffmann, from University of Strasbourg. Dr. Hoffmann discovered a family of cellular receptors, termed “Toll,” in fruit flies that are activated by pathogenic bacteria. Dr. Beutler, a former ASH member and son of the late Ernest Beutler, MD, who was a prominent hematologist and past ASH president, then identified a related family of innate immune receptors in mammalian white blood cells now known as Toll-like receptors (TLRs).

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ASH News Daily - Saturday, December 10, 2011

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