Both hematopoietic failure and development of extramedullary hematopoiesis are associated with disease progression in patients with primary myelofibrosis (PMF). During the previous funding period, close cooperation between Project 4 and 5 led to the identification of striking similarities between stem/progenitor cell (HSC/HPC) and microenvironmental (HM) abnormalities present in PMF patients and Gatallow mice, an animal model for this disease. These abnormalities are potential targets for drug development and we have already identified plitidepsin as a drug that altered the natural history of myelofibrosis in Gatallow mice by targeting both abnormalities. This drug is presently under investigation in Project 6 for the treatment of PMF patients (MPD-RC 110). In this project, we plan to continue the fruitful interaction between Project 4 and 5 by further defining HSC/HPC and HM abnormalities associated with myelofibrosis in Gatallow mice. By transplantation assay and forced gene expression, we propose to test the hypothesis that the hematopoietic failure and development of extramedullary hematopoiesis in Gatallow mice with myelofibrosis is due to autonomous defects of HSC/HPC due to insufficient expression of CXCR4 and/or Rad (respectively the receptor and the first intracellular signaling molecule of the chemokine CXCR12 (Specific aim 1). By immuno-electron microscopy studies and loss of function experiments, we propose to test the hypothesis that, because of alterations in protein sorting into the D-granules, Gatallow MK (and possibly MK from PMF patients) stimulate mesenchymal stem cell maturation into osteoblasts impairing the ability of these cells to form a functional HM in the marrow (Specific aim 2). In addition, in vivo treatments of Gatallow mice with inhibitors of JAK2, the neutrophil protease MMP-9 and TGFD will test the hypothesis that drugs targetting abnormalities in HSC/HPC and HM of Gatal low mice will improve the natural history of myelofibrosis, alone or in combination with plitidepsin, in this animal model of the disease (Specific aim 3),

Public Health Relevance

The beneficial of the majority of drugs that inhibit JAK2 tested in PMF patients up to now are modest, highlighting the importance to identify new treatment strategies for this disease. By using the Gatallow animal model, this study has the potential to further increase our understanding of the patho-biology of PMF and to identify additional targets against which more effective drugs for the treatment of PMF patients can be designed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA108671-08
Application #
8722849
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
$299,320
Indirect Cost
$209,633
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Divoky, Vladimir; Song, Jihyun; Horvathova, Monika et al. (2016) Delayed hemoglobin switching and perinatal neocytolysis in mice with gain-of-function erythropoietin receptor. J Mol Med (Berl) 94:597-608
Spangrude, Gerald J; Lewandowski, Daniel; Martelli, Fabrizio et al. (2016) P-Selectin Sustains Extramedullary Hematopoiesis in the Gata1 low Model of Myelofibrosis. Stem Cells 34:67-82
Migliaccio, Anna Rita (2016) To condition or not to condition-That is the question: The evolution of nonmyeloablative conditions for transplantation. Exp Hematol 44:706-12
Lu, Min; Xia, Lijuan; Liu, Yen-Chun et al. (2015) Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells. Blood 126:972-82
Wang, Xiaoli; Cho, Sool Yeon; Hu, Cing Siang et al. (2015) C-X-C motif chemokine 12 influences the development of extramedullary hematopoiesis in the spleens of myelofibrosis patients. Exp Hematol 43:100-9.e1
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Funnell, Alister P W; Prontera, Paolo; Ottaviani, Valentina et al. (2015) 2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment. Blood 126:89-93
Falchi, Mario; Varricchio, Lilian; Martelli, Fabrizio et al. (2015) Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion. Haematologica 100:178-87

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