KIAA1509 is a novel PDGFRB fusion partner in imatinib-responsive myeloproliferative disease associated with a t(5;14)(q33;q32)

Harvard University, Cambridge, Massachusetts, United States
Leukemia (Impact Factor: 9.38). 02/2005; 19(1):27-30. DOI: 10.1038/sj.leu.2403548
Source: PubMed

ABSTRACT We report the cloning of a novel PDGFRB fusion gene partner in a patient with a chronic myeloproliferative disorder characterized by t(5;14)(q33;q32), who responded to treatment with imatinib mesylate. Fluorescence in situ hybridization demonstrated that PDGFRB was involved in the translocation. Long distance inversion PCR identified KIAA1509 as the PDGFRB fusion partner. KIAA1509 is an uncharacterized gene with a predicted coiled-coil oligomerization domain with homology to the HOOK family of proteins. The predicted KIAA1509-PDGFRbeta fusion protein contains the KIAA1509 coiled-coil domain fused to the cytoplasmic domain of PDGFRbeta that includes the tyrosine kinase domain. Imatinib therapy resulted in rapid normalization of the patient's blood counts, and subsequent bone marrow biopsies and karyotypic analysis were consistent with sustained complete remission.


Available from: Iwona Wlodarska, Jun 03, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Eosinophilia-associated myeloid neoplasms with rearrangement of chromosome bands 5q31-33 are frequently associated with PDGFRB fusion genes, which are exquisitely sensitive to treatment with imatinib. In search for novel fusion partners of PDGFRB, we analyzed three cases with translocation t(5;20)(q33;p11), t(5;14)(q33;q32), and t(5;17;14)(q33;q11;q32) by 5′-rapid amplification of cDNA ends polymerase chain reaction (5′-RACE-PCR) and DNA-based long-distance inverse PCR (LDI-PCR) with primers derived from PDGFRB. LDI-PCR revealed a fusion between CCDC88C exon 25 and PDGFRB exon 11 in the case with t(5;17;14)(q33;q11;q32) while 5′-RACE-PCR identified fusions between CCDC88C exon 10 and PDGFRB exon 12 and between DTD1 exon 4 and PDGFRB exon 12 in the cases with t(5;14)(q33;q32) and t(5;20)(q33;p11), respectively. The PDGFRB tyrosine-kinase domain is predicted to be retained in all three fusion proteins. The partner proteins contained coiled-coil domains or other domains, which putatively lead to constitutive activation of the PDGFRB fusion protein. In vitro functional analyses confirmed transforming activity and imatinib-sensitivity of the fusion proteins. All three patients achieved rapid and durable complete hematologic remissions on imatinib.
    Genes Chromosomes and Cancer 05/2014; 53(5):411-21. DOI:10.1002/gcc.22153 · 3.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Therapy-related myeloid neoplasm after treatment for acute promyelocytic leukemia (APL) is a relatively infrequent but severe complication. Most therapy-related myeloid neoplasms after treatment for APL are classified as therapy-related myelodysplastic syndrome or therapy-related acute myeloid leukemia. Translocation of 5q31-33, PDGFRB occur rarely in therapy-related myeloid neoplasm and there has been two identified PDGFRB partner genes located at 14q32, TRIP11 and KIAA1509. The TRIP11-PDGFRB fusion was identified in a patient with therapy-related myeloid neoplasm with t(5;14)(q33;q32) after treatment of APL using conventional cytogenetics, fluorescence in situ hybridization (FISH) and molecular methods. Cytogenetic analysis of the bone marrow aspirate revealed 46, XY, t(5;14)(q33;q32) in all 20 analyzed cells. No other cytogenetic abnormalities were observed. Break-apart FISH analysis demonstrated that rearrangement of PDGFRB at 5q33 was positive in 460 of 500 cells analyzed, while the PML-RARA rearrangement remained undetectable by RT-PCR. Sequencing of RT-PCR products revealed fusion between exon 16 of TRIP11 and exon 11 of PDGFRB. However, the KIAA1509-PDGFRB fusion was not detected by RT-PCR. We firstly demonstrated that therapy-related myeloid neoplasm with TRIP11-PDGFRB fusion was identified after treatment of APL.
    Molecular Cytogenetics 12/2014; 7(1):103. DOI:10.1186/s13039-014-0103-6 · 2.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: ABSTRACT Protein tyrosine kinases and protein tyrosine phosphatases play pivotal roles in regulation of cellular phosphorylation and signal transduction with opposite functions. Accumulating evidences have uncovered the relevance of genetic alterations in these two family members to hematologic malignancies. This review underlines progress in understanding the pathogenesis of these genetic alterations including mutations and aberrant expression and the evolving protein tyrosine kinases and protein tyrosine phosphatases targeted therapeutic strategies in hematologic neoplasms.
    Future Oncology 02/2015; 11(4):659-673. DOI:10.2217/fon.14.280 · 2.61 Impact Factor