The characterization of constitutional chromosome translocations in specific types of leukemia has consistently led to an understanding of genes important in leukemogenesis. In some cases this information has been translated to the clinical management of the disease, as well as the reliable identification of structural chromosome rearrangements for the classification of tumors, identification of minimal residual disease after treatment and the prediction of relapse before the onset of symptoms. In particular, the timely identification of the presence of specific rearrangements can often determine the aggressiveness of the treatment regimen which should be used. We have recently characterized the ZNF198/FGFR1 fusion tyrosine kinase gene associated with the highly specific 8;13 translocation which is consistently identified in tumors from patients with an atypical myeloproliferative disease which is associated with T-cell lymphoma and may progress to AML. The involvement of both lineages in this disorder suggests that the structural chromosome rearrangement, which is often the only structural chromosome abnormality in the leukemic cells, occurs in an early progenitor cell before the commitment to the myeloid and lymphoid lineages. This fusion event results in the constitutive activation of the FGFR1 kinase domain through dimerization of the ZNF198 zinc finger motif, which results in mislocalization to the cytoplasm. Genetic studies have implicated a number of leukemia related genes associated with the expression of ZNF198/FGFR1 including PML, ABL, HHR6, SOCS3, SSBP2, SUMO1 and PAI2. To gain a better understanding of the pathways involved in ZNF198/FGFR1 induced leukemogenesis we will use a combination of proteomics and cell and molecular biology approaches to characterize the targets of phosphorylation of this chimeric and extend these studies to three variant, FGFR1 activating rearrangements. We have developed an in vivo model of ZNF198/FGFR1 which produces an MPD-like disease following retroviral transfer of the fusion kinase into primary bone marrow cells using an MSCV based vector. Similar models have been created for the other variant rearrangements. These tumors are transplantable to new hosts. Tumors from these mice will be used to investigate the genetic events that contribute to tumor progression. We will use a series of reagents developed for this project to undertake a series of cellular biology analyses designed to characterize the significance of the dysregulated pathways associated with ZNF198/FGFR1 expression. A deeper insight of the molecular consequences of 6

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA076167-10
Application #
8107678
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Howcroft, Thomas K
Project Start
1999-04-01
Project End
2013-01-31
Budget Start
2011-08-01
Budget End
2013-01-31
Support Year
10
Fiscal Year
2011
Total Cost
$277,833
Indirect Cost
Name
Georgia Regents University
Department
Pathology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Cowell, John K; Qin, Haiyan; Hu, Tianxiang et al. (2017) Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas. Int J Cancer 141:1822-1829
Wu, Qing; Bhole, Aaron; Qin, Haiyan et al. (2016) SCLLTargeting FGFR1 to suppress leukemogenesis in syndromic and de novo AML in murine models. Oncotarget 7:49733-49742
Cowell, John K; Qin, Haiyan; Chang, Chang-Sheng et al. (2016) A model of BCR-FGFR1 driven human AML in immunocompromised mice. Br J Haematol 175:542-545
Qin, H; Malek, S; Cowell, J K et al. (2016) Transformation of human CD34+ hematopoietic progenitor cells with DEK-NUP214 induces AML in an immunocompromised mouse model. Oncogene 35:5686-5691
Ren, Mingqiang; Qin, Haiyan; Wu, Qing et al. (2016) Development of ZMYM2-FGFR1 driven AML in human CD34+ cells in immunocompromised mice. Int J Cancer 139:836-40
Qin, Haiyan; Wu, Qing; Cowell, John K et al. (2016) FGFR1OP2-FGFR1 induced myeloid leukemia and T-cell lymphoma in a mouse model. Haematologica 101:e91-4
Ren, Mingqiang; Qin, Haiyan; Kitamura, Eiko et al. (2013) Dysregulated signaling pathways in the development of CNTRL-FGFR1-induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models. Blood 122:1007-16
Ren, M; Qin, H; Ren, R et al. (2013) Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities. Leukemia 27:32-40
Ren, Mingqiang; Tidwell, Josephine A; Sharma, Suash et al. (2012) Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage. PLoS One 7:e38265
Ren, MingQiang; Cowell, John K (2011) Constitutive Notch pathway activation in murine ZMYM2-FGFR1-induced T-cell lymphomas associated with atypical myeloproliferative disease. Blood 117:6837-47

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