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[Cancer Research 60, 3592-3598, July 1, 2000]
© 2000 American Association for Cancer Research

Molecular Biology and Genetics

Fusion of H4/D10S170 to the Platelet-derived Growth Factor Receptor ß in BCR-ABL-negative Myeloproliferative Disorders with a t(5;10)(q33;q21)1

Shashikant Kulkarni, Carol Heath, Sally Parker, Andrew Chase, Sameena Iqbal, Christopher F. Pocock, Jaspal Kaeda, Kate Cwynarski, John M. Goldman and Nicholas C. P. Cross2

Department of Haematology, Imperial College School of Medicine Hammersmith Hospital, London W12 0NN, United Kingdom

We have studied a patient who presented with clinical features suggestive of chronic myeloid leukemia in accelerated phase. BCR-ABL transcripts were undetectable by reverse transcription-PCR, but a novel reciprocal translocation, t(5;10)(q33;q21.2), was seen by standard cytogenetic analysis. Chromosome band 5q33 contains the gene encoding the platelet-derived growth factor ß receptor (PDGFßR), the receptor tyrosine kinase that is disrupted by the t(5;7), t(5;12), and t(5;14) in myeloid disorders, resulting in the fusion of PDGFßR to HIP1, TEL/ETV6, and CEV14, respectively. Southern analysis with PDGFßR cDNA revealed novel bands in patient but not control DNA after digestion with several restriction enzymes, indicating that this gene is also targeted by the t(5;10). Fluorescence in situ hybridization analysis of chromosome 5 indicated that a small inversion at 5q33 had taken place in addition to the interchromosomal translocation. The site of the chromosome 10 breakpoint fell within YAC 940e4. Because all PDGFßR fusions described thus far result in splicing to a common exon of this gene, we performed 5'-rapid amplification of cDNA ends PCR on patient RNA. Several clones were isolated in which PDGFßR fused in frame to H4/D10S170, a previously described ubiquitously expressed gene that is fused to the ret protein tyrosine kinase to form the PTC-1 oncogene in approximately 20% of papillary thyroid carcinomas. The presence of H4-PDGFßR chimeric mRNA in the patient was confirmed by reverse transcription-PCR; reciprocal PDGFßR-H4 transcripts were not detected. We conclude that t(5;10)(q33;q21.2) is a novel translocation in BCR-ABL-negative chronic myeloid leukemia and that this abnormality results in an H4-PDGFßR fusion gene. This finding further strengthens the association between myeloproliferative disorders and deregulated tyrosine kinases.




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