H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22)

Citation
J. Schwaller et al., H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22), BLOOD, 97(12), 2001, pp. 3910-3918
Citations number
48
Categorie Soggetti
Hematology,"Cardiovascular & Hematology Research
Journal title
BLOOD
ISSN journal
00064971 → ACNP
Volume
97
Issue
12
Year of publication
2001
Pages
3910 - 3918
Database
ISI
SICI code
0006-4971(20010615)97:12<3910:HAGFRI>2.0.ZU;2-8
Abstract
The molecular cloning of the t(5;10)(q33; q22) associated with atypical chr onic 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-de rived growth factor receptor betaR (PDGF betaR) fusion transcript that inco rporated 5 ' sequences from H4 fused in frame to 3 ' PDGF betaR sequences e ncoding the transmembrane, WW-like, and tyrosine kinase domains. FISH combi ned 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(+) cell s. H4 has previously been implicated in pathogenesis of papillary thyroid c arcinoma as a fusion partner of RET, The H4/RET fusion incorporates 101 ami no acids of H4, predicted to encode a leucine zipper dimerization domain, w hereas the H4/PDGF betaR fusion incorporated an additional 267 amino acids of H4, Retroviral transduction of H4/PDGF betaR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-c ell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation. Mutational analysis showed that the amino-terminal H4 leuc ine 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/F 3 cells. Tryptophan-to-alanine substitutions in the PDGF betaR WW-like doma in at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGF betaR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGF betaR is an oncoprotein expressed in t(5;10)(q33;q22) atypical CML and requires dimerization motifs in the H4 moiety, as well as residues imp licated in signal transduction by PDGFPR, for efficient induction of factor -independent growth of Ba/F3 cells, (C) 2001 by The American Society of Hem atology.