Genetic and functional data have demonstrated the importance of somatic mutations in signaling effectors and in epigenetic modifiers in the pathogenesis of myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). However, the mechanisms by which these two classes of leukemia disease alleles cooperate to induce transformation, and how coordinate mutations in signaling pathways and in epigenetic regulators affect the response to targeted therapy, has not been fully elucidated. Here we propose to investigate how mutations in signaling effectors cooperate with mutations in epigenetic regulators to induce myeloid transformation, and how these mutations influence the response to targeted therapies including the development of therapeutic resistance. We will then extend our studies to investigate whether combination therapeutic approaches can achieve increased efficacy in models of myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). The long-term goals of this proposal are to characterize novel mechanisms by which oncogenic disease alleles cooperate to induce leukemogenesis, and to credential novel combination strategies that can be investigated in the clinical context. We will investigate this using a combination of novel, genetically accurate animal models, epigenomic studies in murine models and patient samples, and preclinical therapeutic studies aimed at rational design of combination therapeutic strategies. Our studies have a mechanistic focus, but are aimed to rapidly translate these insights to the clinical context.

Public Health Relevance

This proposal outlines a series of specific aims focused on delineating the intersection between mutations in oncogenic signaling pathways and somatic alterations in epigenetic regulators, which are commonly co- mutated in myeloid malignancies and in other tumor types. We propose to use a combination of novel, genetically accurate animal models, epigenomic studies in murine models and patient samples, and preclinical therapeutic studies aimed at rational design of combination therapeutic strategies. Our studies have a mechanistic focus, but also are aimed to rapidly translate these insights to the clinical context.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
1R35CA197594-01A1
Application #
9186811
Study Section
Special Emphasis Panel (ZCA1-GRB-I (M2))
Program Officer
Mufson, R Allan
Project Start
2017-01-17
Project End
2023-12-31
Budget Start
2017-01-17
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
$1,028,400
Indirect Cost
$428,400
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
Research Institutes
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Intlekofer, Andrew M; Shih, Alan H; Wang, Bo et al. (2018) Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature 559:125-129
Kleppe, Maria; Spitzer, Matthew H; Li, Sheng et al. (2018) Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis. Cell Stem Cell 22:277
Busque, Lambert; Buscarlet, Manuel; Mollica, Luigina et al. (2018) Concise Review: Age-Related Clonal Hematopoiesis: Stem Cells Tempting the Devil. Stem Cells 36:1287-1294
Kleppe, Maria; Koche, Richard; Zou, Lihua et al. (2018) Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. Cancer Cell 33:785-787
Bowman, Robert L; Busque, Lambert; Levine, Ross L (2018) Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell 22:157-170
McKenney, Anna Sophia; Lau, Allison N; Somasundara, Amritha Varshini Hanasoge et al. (2018) JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest 128:789-804
Pronier, Elodie; Cifani, Paolo; Merlinsky, Tiffany R et al. (2018) Targeting the CALR interactome in myeloproliferative neoplasms. JCI Insight 3:
Harding, James J; Lowery, Maeve A; Shih, Alan H et al. (2018) Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition. Cancer Discov 8:1540-1547
Pronier, Elodie; Bowman, Robert L; Ahn, Jihae et al. (2018) Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis. Blood 132:1265-1278

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