Primary myelofibrosis (PMF) is associated with abnormal trafficking pattems of CD34+ ceils, wtiicli fias been attributed to dysregulation of the bone marrow microenvironment due to downregulation of the chemokine receptor, CXCR4 by CD34+ cells, production by PIVIF cells of a variety proteases including matrix metaIloproteinase-9 (i /IMP-9), neutrophil elastase (NE), cathepsin G (CG) and CD26, which disrupt the interactions between chemoldne receptors and integrins expressed by CD34+ cells and chemokines and matrix proteins produced by the manrow microenvironment, distortion of the marrow architecture by fibrosis and incrased marrow microvessel density. Furthermore, the marrows of these patients are exposed to a variety of cytokines many of which have a profound effect on both cells belonging to the maaow microenvironment and hematopoietic stem cells (HSC)/hematopoietic progenitor cells (HPC). We hypothesize that distinctive hematopoietic microenvironments are present in the spleen and marrow of PMF patients which differentially influence PMF-HSC/HPC proliferation and trafficking thereby determining disease phenotype and progression. This hypothesis is based upon the assumption that stem cell niches within the marrow and spleen of PMF patients which nurture and determine stem cell fate decisions are dysfunctional as a consequence of their close interactions with PMF cells and that such cancer activates niches are capable of influencing PMF HSC/HPC behavior. In order to test this hypothesis the following specific aims will be pursued: 1: We will test the hypothesis that the hematopoietic microenvironment in the marrows and spleens of MPN MF patients each have distinctive charateristics which determine CD34+ cell trafficing patterns. 2) We will test the hypothesis that the interplay between PMF and their progeny and components of the microenvironment within the marrow leads to dysregulated cancer niches allowing HSC/HPC to escape the tightly regulated proliferation signals which normally occur. These dysfunctional hematopoietic niches in PMF ultimately contribute to depletion of marrow HSC/HPS and the survival of malignant clones endowed with a higher affinity for niches within the spleen resulting in disease progression.

Public Health Relevance

We hypothesize that distinctive hematopoietic microenvironments are present in the spleen and man-ow of PMF patients which differentially influence PMF-HSC/HPC proliferation. With the completion of these studies we anticipate a paradigm shift in the treatment of MPN MF moving beyond the exclusive use of agents to target cells belonging to the malignant clone to a strategy combining the use of such drugs with agents that interfere with the dysfunctional hematonopoietic microenvironment

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA108671-06
Application #
8377875
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2012
Total Cost
$430,631
Indirect Cost
$123,168
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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