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Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2001, Vol. 97, No. 12, pp. 3910-3918 NEOPLASIA H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor  gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22) Juerg Schwaller, Ema Anastasiadou, Danielle Cain, Jeff Kutok, Sarah Wojiski, Ifor R. Williams, Roberta LaStarza, Barbara Crescenzi, David W. Sternberg, Patrick Andreasson, Roberta Schiavo, Salvatore Siena, Cristina Mecucci, and D. Gary Gilliland From the Division of Hematology, Department of Medicine, and the Department of Pathology, Brigham and Women's Hospital, and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; the Department of Pathology, Emory University, Atlanta, GA; Divisione di Oncologia-Ematologia, Ospedale Niguarda Ca' Granda, Milan, and Sezione di Ematologia, Università degli studi di Perugia, Italy. The molecular cloning of the t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia (CML) is reported. Fluorescence in situ hybridization (FISH), Southern blot, and reverse transcriptase- polymerase chain reaction analysis demonstrated that the translocation resulted in an H4/platelet-derived growth factor receptor R (PDGFR) fusion transcript that incorporated 5' sequences from H4 fused in frame to 3' PDGFR sequences encoding the transmembrane, WW-like, and tyrosine kinase domains. FISH combined with immunophenotype analysis showed that t(5;10)(q33;q22) was present in CD13+ and CD14+ cells but was not observed in CD3+ or CD19+ cells. H4 has previously been implicated in pathogenesis of papillary thyroid carcinoma as a fusion partner of RET. The H4/RET fusion incorporates 101 amino acids of H4, predicted to encode a leucine zipper dimerization domain, whereas the H4/PDGFR fusion incorporated an additional 267 amino acids of H4. Retroviral transduction of H4/PDGFR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-cell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation. Mutational analysis showed that the amino-terminal H4 leucine zipper domain (amino acids 55-93), as well as H4 amino acids 101 to 386, was required for efficient induction of factor-independent growth of Ba/F3 cells. Tryptophan-to-alanine substitutions in the PDGFR WW-like domain at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGFR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGFR is an oncoprotein expressed in t(5;10)(q33;q22) atypical CML and requires dimerization motifs in the H4 moiety, as well as residues implicated in signal transduction by PDGFR, for efficient induction of factor-independent growth of Ba/F3 cells. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. Dubois, F. Vandermoere, A. Gernez, J. Murphy, R. Toth, S. Chen, K. M. Geraghty, N. A. Morrice, and C. MacKintosh Differential 14-3-3 Affinity Capture Reveals New Downstream Targets of Phosphatidylinositol 3-Kinase Signaling Mol. Cell. Proteomics, November 1, 2009; 8(11): 2487 - 2499. [Abstract] [Full Text] [PDF] M. Adam, V. Pogacic, M. Bendit, R. 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