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)

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4419-4426 ◽  
Author(s):  
Theodora S. Ross ◽  
Olivier A. Bernard ◽  
Roland Berger ◽  
D. Gary Gilliland
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Bone Marrow Cells ◽  
Fusion Gene ◽  
Chronic Myelomonocytic Leukemia ◽  
Platelet Derived Growth Factor ◽  
Gene Probe ◽  
Alternative Mechanism ◽  
Interacting Protein ◽  
Myelomonocytic Leukemia

Abstract We report the fusion of the Huntingtin interactin protein 1(HIP1) gene to the platelet-derived growth factor βreceptor (PDGFβR) 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 PDGFβR gene probe demonstrated rearrangement of the PDGFβR gene. Anchored polymerase chain reaction using PDGFβRprimers identified a chimeric transcript containing the HIP1gene located at 7q11.2 fused to the PDGFβR 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/PDGFβR fusion gene that encodes amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFβR. The reciprocalPDGFβR/HIP1 transcript is not expressed. HIP1/PDGFβR is a 180-kD protein when expressed in the murine hematopoietic cell line, Ba/F3, and is constitutively tyrosine phosphorylated. Furthermore, HIP1/PDGFβR transforms the Ba/F3 cells to interleukin-3–independent growth. These data are consistent with an alternative mechanism for activation of PDGFβR 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.

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)

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4419-4426 ◽  
Author(s):  
Theodora S. Ross ◽  
Olivier A. Bernard ◽  
Roland Berger ◽  
D. Gary Gilliland
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Bone Marrow Cells ◽  
Fusion Gene ◽  
Chronic Myelomonocytic Leukemia ◽  
Platelet Derived Growth Factor ◽  
Gene Probe ◽  
Alternative Mechanism ◽  
Interacting Protein ◽  
Myelomonocytic Leukemia

We report the fusion of the Huntingtin interactin protein 1(HIP1) gene to the platelet-derived growth factor βreceptor (PDGFβR) 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 PDGFβR gene probe demonstrated rearrangement of the PDGFβR gene. Anchored polymerase chain reaction using PDGFβRprimers identified a chimeric transcript containing the HIP1gene located at 7q11.2 fused to the PDGFβR 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/PDGFβR fusion gene that encodes amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFβR. The reciprocalPDGFβR/HIP1 transcript is not expressed. HIP1/PDGFβR is a 180-kD protein when expressed in the murine hematopoietic cell line, Ba/F3, and is constitutively tyrosine phosphorylated. Furthermore, HIP1/PDGFβR transforms the Ba/F3 cells to interleukin-3–independent growth. These data are consistent with an alternative mechanism for activation of PDGFβR 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.

Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor β receptor fusion oncogene

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 1088-1091 ◽  
Author(s):  
Magnus K. Magnusson ◽  
Kristin E. Meade ◽  
Ryotaro Nakamura ◽  
John Barrett ◽  
Cynthia E. Dunbar
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Chronic Myelomonocytic Leukemia ◽  
Platelet Derived Growth Factor ◽  
Gene Transcript ◽  
Molecular Remission ◽  
Β Receptor ◽  
Myelomonocytic Leukemia

Abstract Platelet-derived growth factor β receptor (PDGFβR) fusion genes have been shown to be critical transforming oncogenes in a subset of patients with chronic myelomonocytic leukemia (CMML). The sensitivity of dysregulated tyrosine kinase oncogenes to the tyrosine kinase inhibitor STI571 (imatinib mesylate) makes it a potentially attractive treatment option in this subset of patients. We have recently cloned a novel member of the PDGFβR fusion oncogene family, rabaptin-5-PDGFβR. A patient with CMML carrying the rabaptin-5-PDGFβR fusion gene underwent allogeneic stem cell transplantation (SCT) and was monitored closely with a sensitive reverse transcriptase–polymerase chain assay to detect the novel fusion gene transcript. After achieving a molecular remission at 5 months after transplantation, 15 months after SCT the patient showed persistent and progressive evidence of molecular relapse. After demonstrating in vitro that cells transformed with this specific fusion oncogene are efficiently killed by STI571, the patient was started on STI571. The patient responded rapidly and entered molecular remission after 6 weeks of therapy, and he continues to be in remission 6 months later. These results suggest that STI571 may be an effective targeted therapy in patients with CMML related to PDGFβR fusion oncogenes.

Rabaptin-5 is a novel fusion partner to platelet-derived growth factor β receptor in chronic myelomonocytic leukemia

Blood ◽  
2001 ◽  
Vol 98 (8) ◽  
pp. 2518-2525 ◽  
Author(s):  
Magnus K. Magnusson ◽  
Kristin E. Meade ◽  
Kevin E. Brown ◽  
Diane C. Arthur ◽  
Lisa A. Krueger ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fusion Protein ◽  
Tyrosine Kinase ◽  
Fusion Proteins ◽  
Growth Regulation ◽  
Chronic Myelomonocytic Leukemia ◽  
Platelet Derived Growth Factor ◽  
Fusion Partner ◽  
Β Receptor ◽  
Myelomonocytic Leukemia

Abstract Chromosomal translocations involving the platelet-derived growth factor β receptor (PDGFβR) gene have been reported in some patients with chronic myelomonocytic leukemia (CMML). The resultant fusion proteins have constitutive PDGFβR tyrosine kinase activity, but the partner genes previously reported(tel, Huntingtin interacting protein 1[HIP-1], H4/D10S170) have poorly understood roles in the oncogenic activity of the fusion proteins. A novel PDGFβR fusion protein has been characterized in a patient with CMML and an acquired t(5;17)(q33;p13). Southern blot analysis on patient leukemia cells demonstrated involvement of the PDGFβR gene. Using 5′ rapid amplification of complementary DNA ends–polymerase chain reaction (RACE-PCR) on patient RNA, rabaptin-5 was identified as a novel partner fused in-frame to thePDGFβR gene. The new fusion protein includes more than 85% of the native Rabaptin-5 fused to the transmembrane and intracellular tyrosine kinase domains of the PDGFβR. Transduction with a retroviral vector expressing rabaptin-5/PDGFβRtransformed the hematopoietic cell line Ba/F3 to growth factor independence and caused a fatal myeloproliferative disease in mice. Rabaptin-5 is a well-studied protein shown to be an essential and rate-limiting component of early endosomal fusion through interaction with the Ras family GTPases Rab5 and Rab4. The fusion protein includes 3 of 4 coiled-coil domains (involved in homodimerization of native rabaptin-5), 2 caspase-3 cleavage sites, and a binding site for the tumor suppressor gene tuberin (tuberous sclerosis complex-2). Early endosomal transport is critical in regulation of various growth factor receptors, through ligand-induced clathrin-mediated endocytosis, and thus this new fusion protein links together 2 important pathways of growth regulation.

Molecular Targeting of Platelet-Derived Growth Factor B by Imatinib Mesylate in a Patient With Metastatic Dermatofibrosarcoma Protuberans

2002 ◽  
Vol 20 (17) ◽  
pp. 3586-3591 ◽  
Author(s):  
Brian P. Rubin ◽  
Scott M. Schuetze ◽  
Janet F. Eary ◽  
Thomas H. Norwood ◽  
Sohail Mirza ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Dermatofibrosarcoma Protuberans ◽  
Response To Therapy ◽  
Platelet Derived Growth Factor ◽  
Response To Treatment ◽  
Resected Specimen ◽  
Factor B

PURPOSE: Dermatofibrosarcoma protuberans is caused by activation of the platelet-derived growth factor B (PDGFB) receptor, a transmembrane tyrosine kinase. We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate. PATIENTS AND METHODS: A patient with unresectable, metastatic dermatofibrosarcoma protuberans received imatinib mesylate (400 mg bid). Response to therapy was assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography, magnetic resonance imaging, and histopathologic and immunohistochemical evaluation. RESULTS: The patient was treated for 4 months with imatinib mesylate. The hypermetabolic uptake of FDG fell to background levels within 2 weeks of treatment, and the tumor volume shrank by over 75% during the 4 months of therapy, allowing for resection of the mass. There was no residual viable tumor in the resected specimen, indicating a complete histologic response to treatment with imatinib mesylate. CONCLUSION: Imatinib mesylate is highly active in dermatofibrosarcoma protuberans. The dramatic response seen in this patient demonstrates that inhibition of PDGFB receptor tyrosine kinase activity can significantly impact viability of at least one type of solid tumor.

Activation of the small GTP-binding proteins rho and rac by growth factor receptors

1995 ◽  
Vol 108 (1) ◽  
pp. 225-233 ◽  
Author(s):  
C.D. Nobes ◽  
P. Hawkins ◽  
L. Stephens ◽  
A. Hall
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Phorbol Ester ◽  
Lysophosphatidic Acid ◽  
Actin Polymerization ◽  
Binding Proteins ◽  
Platelet Derived Growth Factor ◽  
Gtp Binding ◽  
Rho Protein

The small GTP-binding proteins, rho and rac, control signal transduction pathways that link growth factor receptors to the activation of actin polymerization. In Swiss 3T3 cells, rho proteins mediate the lysophosphatidic acid and bombesin-induced formation of focal adhesions and actin stress fibres, whilst rac proteins are required for the platelet-derived growth factor-, insulin-, bombesin- and phorbol ester (phorbol 12-myristate 13-acetate)-stimulated actin polymerization at the plasma membrane that results in membrane ruffling. To investigate the role of p85/p110 phosphatidylinositol 3-kinase in the rho and rac signalling pathways, we have used a potent inhibitor of this activity, wortmannin. Wortmannin has no effect on focal adhesion or actin stress fibre formation induced by lysophosphatidic acid, bombesin or microinjected recombinant rho protein. In contrast, it totally inhibits plasma membrane edge-ruffling induced by platelet-derived growth factor and insulin though not by bombesin, phorbol ester or microinjected recombinant rac protein. We conclude that phosphatidylinositol 3,4,5 trisphosphate mediates activation of rac by the platelet-derived growth factor and insulin receptors. The effects of lysophosphatidic acid on the Swiss 3T3 actin cytoskeleton can be blocked by the tyrosine kinase inhibitor, tyrphostin. Since tyrphostin does not inhibit the effects of microinjected rho protein, we conclude that lysophosphatidic acid activation of rho is mediated by a tyrosine kinase.

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