Abstract 3175: Genomic and transcriptomic data integration in chronic myelomonocytic leukemia reveals a novel fusion gene involving onco-miR-125b-2

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.

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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 ◽

10.1182/blood.v91.12.4419.412k43_4419_4426 ◽

1998 ◽

Vol 91 (12) ◽

pp. 4419-4426 ◽

Cited By ~ 2

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.

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AML1/RUNX1 fusion gene and t(5;21)(q13;q22) in a case of chronic myelomonocytic leukemia with progressive thrombocytopenia and monocytosis

Cancer Genetics and Cytogenetics ◽

10.1016/j.cancergencyto.2003.11.002 ◽

2004 ◽

Vol 152 (2) ◽

pp. 172-174 ◽

Cited By ~ 6

Author(s):

Shihe Liu ◽

Chengwen Li ◽

Lijin Bo ◽

Yun Dai ◽

Zhijian Xiao ◽

...

Keyword(s):

Fusion Gene ◽

Chronic Myelomonocytic Leukemia ◽

Myelomonocytic Leukemia

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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 ◽

10.1182/blood.v91.12.4419 ◽

1998 ◽

Vol 91 (12) ◽

pp. 4419-4426 ◽

Cited By ~ 128

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.

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