Fusion of Huntingtin Interacting protein 1 to platelet-derived growth factor β receptor (PDGFβR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2)

We report the fusion of the Huntingtin interactin protein I (HIP1) gene to the platelet-derived growth factor Preceptor (PDGF beta R) gene in a patient with chronic myelomonocytic leukemia (CMML) with a t(5;7)(q33;q11.2) translocation. Southern blot analysis of patient bone marrow cells with a PDGF beta R gene probe demonstrated rearrangement of the PDGF beta R gene. Anchored polymerase chain reaction using PDGF beta R primers identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGF beta R gene on 5q33. HIP1 is a 116-kD protein recently cloned by yeast two-hybrid screening for proteins that interact with Huntingtin, the mutated protein in Huntington's disease. The consequence of t(5;7)(q33;q11.2) is an HIP1/PDGF beta R fusion gene that encodes amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGF beta R. The reciprocal PDGF beta R/HIP1 transcript is not expressed, HIP1/PDGF beta R is a 180-kD protein when expressed in the murine hematopoietic cell line, Ba/F3, and is constitutively tyrosine phosphorylated. Furthermore, HIP1/PDGF beta R transforms the Ba/F3 cells to interleukin-3-independent growth, These data are consistent with an alternative mechanism for activation of PDGF beta R tyrosine kinase activity by fusion with HIP1, leading to transformation of hematopoietic cells, and may implicate Huntingtin or HIP1 in the pathogenesis of hematopoietic malignancies. (C) 1998 by The American Society of Hematology.