notch ankyrin repeat domain variation influences leukemogenesis and myc transactivation切口锚蛋白重复域变化影响白血病生成和myc transactivation.pdfVIP

Notch Ankyrin Repeat Domain Variation Influences Leukemogenesis and Myc Transactivation 1 3,4 2 2 2 2 Jon C. Aster *, Nick Bodnar , Lanwei Xu , Fredrick Karnell , John M. Milholland , Ivan Maillard , Gavin 1 4 1,3,4 2 Histen , Yunsun Nam , Stephen C. Blacklow , Warren S. Pear * 1 Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America, 2 Department of Pathology and Lab Medicine, Abramson Family Cancer Research Institute, Institute for Medicine and Engineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America, 4 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Background: The functional interchangeability of mammalian Notch receptors (Notch1-4) in normal and pathophysiologic contexts such as cancer is unsettled. We used complementary in vivo, cell-based and structural analyses to compare the abilities of activated Notch1-4 to support T cell development, induce T cell acute lymphoblastic leukemia/lymphoma (T- ALL), and maintain T-ALL cell growth and survival. Principal Findings: We find that the activated intracellular domains of Notch1-4 (ICN1-4) all support T cell development in mice and thymic organ culture. However, unlike ICN1-3, ICN4 fails to induce T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and is unable to rescue the growth of Notch1-dependent T-ALL cell lines. The ICN4 phenotype is mimicked by weak