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).

Abstract

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 betaR (PDGFbetaR) fusion transcript that incorporated 5' sequences from H4 fused in frame to 3' PDGFbetaR 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/PDGFbetaR fusion incorporated an additional 267 amino acids of H4. Retroviral transduction of H4/PDGFbetaR, 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 PDGFbetaR WW-like domain at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGFbetaR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGFbetaR 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 PDGFbetaR, for efficient induction of factor-independent growth of Ba/F3 cells. (Blood. 2001;97:3910-3918)

• Authors: J Schwaller, E Anastasiadou, D Cain, J Kutok, S Wojiski, I R Williams, R LaStarza, B Crescenzi, D W Sternberg, P Andreasson, R Schiavo, S Siena, C Mecucci, D G Gilliland
• Journal: Blood (Blood) Vol. 97 Issue 12 Pg. 3910-8 (Jun 15 2001) ISSN: 0006-4971 [Print] United States
• PMID: 11389034 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CCDC6 protein, human
• Cytoskeletal Proteins
• DNA, Neoplasm
• Oncogene Proteins, Fusion
• Proteins
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Carcinoma, Papillary (genetics)
• Cell Transformation, Neoplastic (genetics)
• Chromosomes, Human, Pair 10 (genetics)
• Chromosomes, Human, Pair 5 (genetics)
• Cloning, Molecular
• Cytogenetic Analysis
• Cytoskeletal Proteins
• DNA, Neoplasm (genetics, isolation & purification)
• Gene Rearrangement
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (etiology, genetics, pathology)
• Mutagenesis
• Myeloid Cells (metabolism, pathology)
• Oncogene Proteins, Fusion
• Protein Structure, Tertiary
• Proteins (genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (genetics)
• Thyroid Neoplasms (genetics)
• Transfection
• Translocation, Genetic