Myeloproliferative neoplasms (MPN) are diseases that are characterized by overproduction of mature blood cells. These diseases are commonly characterized by somatic activating mutations in the Janus Kinase 2 (JAK2) pathway, including mutations in the JAK2 protein itself (JAK2V617F) or in the coexpressed thrombopoietin receptor MPLW515L/K. The most feared complication of MPN is the transformation to acute myeloid leukemia (AML) - patients with leukemic progression show a median survival of less than six months and ultimate mortality of 98%. Conventional anti-leukemic therapies have demonstrated little efficacy in patients with MPN who develop AML, and no therapy has been demonstrated beyond supportive care for these patients, indicating a powerful need for new models and improved approaches toward therapy of this disease. Because patients with MPN usually present to the clinic before they progress to leukemia, samples from patients taken before and after progression allow us to dissect the sequence of genomic and epigenomic events that are associated with leukemic transformation. In patient samples, mutations in the isocitrate dehydrogenase (IDH) and TET2 proteins, which are functionally related epigenetic effectors, have been associated with this transformation and significantly reduced leukemia-free survival. To date, no models of transformation from MPN to AML have been developed, and there are no published data investigating leukemic cooperativity between JAK2 and IDH mutations in vivo. In order to advance our understanding of the sequential events in leukemogenesis and improve therapeutic options for Post-MPN AML patients, we will explore this process through three approaches. Human samples of paired chronic phase and post-MPN AML samples will be examined using genetic and epigenetic studies to assess the impact of specific mutations on leukemic transformation. In vitro models, including cell lines and primary bone marrow cells, will be used to assess the epigenetic and signaling aberrations that occur at the time of transformation. Finally, a mouse model of leukemic transformation will be generated by expressing JAK2V617F and IDH mutations in a temporal and spatially controlled manner. This model will be subsequently used to assess the efficacy of JAK-STAT and IDH inhibitors, alone and in combination, to determine if targeting multiple oncogenic disease alleles results in increased drug efficacy. The approaches in this proposal provide platforms to train an aspiring MD-PhD scientist in translational biology using clinical genomics and biological models.

Public Health Relevance

Certain blood diseases (myeloproliferative neoplasms) can evolve into a particularly deadly form of leukemia that has no effective therapy. To help these patients, we compare their blood samples before and after they acquire leukemia to understand why this progression happens. With this information, we can simultaneously help find new therapies for these patients and learn more about the fundamental processes by which cancer evolves.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA183497-04
Application #
9207432
Study Section
Special Emphasis Panel (ZRG1-F09A-L (20)L)
Program Officer
Damico, Mark W
Project Start
2014-02-07
Project End
2018-02-06
Budget Start
2017-02-07
Budget End
2018-02-06
Support Year
4
Fiscal Year
2017
Total Cost
$48,576
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Administration
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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
Hobbs, Gabriela S; Hanasoge Somasundara, Amritha Varshini; Kleppe, Maria et al. (2018) Hsp90 inhibition disrupts JAK-STAT signaling and leads to reductions in splenomegaly in patients with myeloproliferative neoplasms. Haematologica 103:e5-e9
Kunimoto, Hiroyoshi; McKenney, Anna Sophia; Meydan, Cem et al. (2017) Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells. Blood 129:1779-1790
Guryanova, Olga A; Shank, Kaitlyn; Spitzer, Barbara et al. (2016) DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nat Med 22:1488-1495
Meyer, Sara C; Keller, Matthew D; Chiu, Sophia et al. (2015) CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms. Cancer Cell 28:15-28
Kleppe, Maria; Kwak, Minsuk; Koppikar, Priya et al. (2015) JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response. Cancer Discov 5:316-31
Rampal, Raajit; Ahn, Jihae; Abdel-Wahab, Omar et al. (2014) Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. Proc Natl Acad Sci U S A 111:E5401-10
McKenney, Anna Sophia; Levine, Ross L (2013) Isocitrate dehydrogenase mutations in leukemia. J Clin Invest 123:3672-7