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 #
1P01CA066996-03
Application #
6269693
Study Section
Project Start
1998-05-14
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
1998
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

Hogan, Louise E; Körner, Christian; Hobbs, Kristen et al. (2018) NK-cell activation is associated with increased HIV transcriptional activity following allogeneic hematopoietic cell transplantation. Blood Adv 2:1412-1416
Kelly, Rachel S; Lasky-Su, Jessica; Yeung, Sai-Ching J et al. (2018) Integrative omics to detect bacteremia in patients with febrile neutropenia. PLoS One 13:e0197049
Nakamura, Makoto; Wu, Lizi; Griffin, James D et al. (2018) Notch1 activation enhances proliferation via activation of cdc2 and delays differentiation of myeloid progenitors. Leuk Res 72:34-44
Gechijian, Lara N; Buckley, Dennis L; Lawlor, Matthew A et al. (2018) Functional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands. Nat Chem Biol 14:405-412
Sridhar, Radhakrishnan; Takei, Hisashi; Syed, Riyaz et al. (2018) Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBP?. Molecules 23:
Chu, S Haihua; Song, Evelyn J; Chabon, Jonathan R et al. (2018) Inhibition of MEK and ATR is effective in a B-cell acute lymphoblastic leukemia model driven by Mll-Af4 and activated Ras. Blood Adv 2:2478-2490
Wang, Jinhua; Erazo, Tatiana; Ferguson, Fleur M et al. (2018) Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains. ACS Chem Biol 13:2438-2448
Sievers, Quinlan L; Gasser, Jessica A; Cowley, Glenn S et al. (2018) Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 132:1293-1303
Cortes, Jorge E; Douglas Smith, B; Wang, Eunice S et al. (2018) Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol 93:1301-1310
Fathi, Amir T; Erba, Harry P; Lancet, Jeffrey E et al. (2018) A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML. Blood 132:1125-1133

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