Abstract

This project will characterize the role of tyrosine kinase fusions in pathogenesis of hematologic malignancy, through development of murine models of leukemia and lymphoma. Our laboratory has recently cloned several tyrosine kinase fusions which will provide the basis for these studies. We have cloned the TEL-PDGFRbeta fusion and related variants associated with t(5;12) chronic myelomonocytic leukemia (CMML), and a novel TEL-ABL fusion associated with acute myeloid leukemia. Our collaborator, has cloned athe NPM-ALK tyrosine kinase fusion associated with high grade lymphomas. We will develop murine models of leukemia and lymphoma using the TEL-PDGFRbeta, TEL-ABL and NPM-ALK fusions. As with BCR-ABL in chronic myelogenous leukemia (CML), TEL-PDGFRbeta, TEL- ABL and NPM-ALK may confer a malignant phenotype by constitutive activation of the tyrosine kinase domains of PDGFRbeta and ALK.
In Specific Aim 1 we will characterize involvement of TEL and PDGFRbeta in patients with (i) CMML and t(5;12) translocation, (ii) CMML with normal karyotype, (iii) other FAB subtypes of myelodysplastic syndrome, (iv) myeloid metaplasia and myelofibrosis, (v), acute monocytic leukemias, and (vi) hematologic malignancy with 12p13 cytogenetic abnormalities. These studies will help to clarify the role of TEL and PDGFRbeta in pathogenesis of hematologic malignancy, and may provide insight into functional domains which are important in transforming activity.
In Specific Aim 2, transforming activity of the TEL-PDGFRbeta and TEL-ABL fusion gene will be confirmed in stably transfected mammalian cell lines. Expression of TEL-PDGFRbeta and TEL-ABL fusions will be confirmed by immunoblotting and in vitro kinase assays.
Specific Aims 1 and 2 will provide the basis for Specific Aim 3 will assess transforming potential of the TEL-PDGFRbeta, TEL-ABL and NPM- ALK fusions in murine bone marrow transplant models of leukemia and lymphoma. Evaluation of transplanted mice will include detailed histopathologic examination; white blood cell differential and immunophenotype analysis to determine lineage involvement of hematological malignancy; and analysis of leukemic cells and leukemic cell lines from transplanted mice for evidence of proviral integration and expression of the fusion protein. These studies will characterize the role of the TEL- PDGFRbeta, TEL-ABL and NPM-ALK fusion proteins in pathogenesis of leukemia and lymphoma, and may provide insight into more effective therapy of hematologic malignancy mediated by tyrosine kinase fusions. Furthermore, these studies will provide a foundation for immunotherapeutic approaches to leukemia and lymphoma.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA066996-02
Application #
6237539
Study Section
Project Start
1997-04-25
Project End
1998-03-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Hemming, Matthew L; Lawlor, Matthew A; Zeid, Rhamy et al. (2018) Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome. Proc Natl Acad Sci U S A 115:E5746-E5755
Kardosova, Miroslava; Zjablovskaja, Polina; Danek, Petr et al. (2018) C/EBP? is dispensable for steady-state and emergency granulopoiesis. Haematologica 103:e331-e335
Numata, Akihiko; Kwok, Hui Si; Kawasaki, Akira et al. (2018) The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Nat Commun 9:1622
Brown, Fiona C; Still, Eric; Koche, Richard P et al. (2018) MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. Cancer Discov 8:478-497
Manley, Paul W; Weisberg, Ellen; Sattler, Martin et al. (2018) Midostaurin, a Natural Product-Derived Kinase Inhibitor Recently Approved for the Treatment of Hematological MalignanciesPublished as part of the Biochemistry series ""Biochemistry to Bedside"". Biochemistry 57:477-478
Ebert, Benjamin L; Libby, Peter (2018) Clonal Hematopoiesis Confers Predisposition to Both Cardiovascular Disease and Cancer: A Newly Recognized Link Between Two Major Killers. Ann Intern Med 169:116-117
DiNardo, Courtney D; Pratz, Keith W; Letai, Anthony et al. (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19:216-228
Brien, Gerard L; Remillard, David; Shi, Junwei et al. (2018) Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. Elife 7:
Weinberg, Olga K; Gibson, Christopher J; Blonquist, Traci M et al. (2018) Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities. Haematologica 103:626-633
Hoshii, Takayuki; Cifani, Paolo; Feng, Zhaohui et al. (2018) A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell 172:1007-1021.e17

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