The myelodysplastic syndromes (MDS) are the most common myeloid neoplasm in the U.S. They are hallmarked by bone marrow failure due to ineffective hematopoiesis and production of dysplastic blood cells, resulting in anemia, leukopenia, and/or thrombocytopenia and a high risk of transformation to acute leukemia. Overall survival is poor as the current standard of care is inadequate, relying largely on symptomatic management of cytopenias and limited drugs with low response rates and durability. As MDS predominately affects older adults, disease prevalence will likely increase with the growing aged population, underscoring the crucial need now to identify new therapeutic targets in MDS. We and others have demonstrated that alterations of the bone marrow microenvironment (BMME) in MDS contribute to hematopoietic failure and disease progression. The BMME normally regulates hematopoietic stem cells to ensure life-long production of blood cells while preventing neoplastic disease. Although in vitro evidence suggests that marrow stromal cells are dysfunctional in the MDS BMME and have an impaired ability to support hematopoiesis, the mechanism of BMME dysfunction remains unknown due to the lack of robust in vivo studies on the interactions between MDS hematopoietic cells and their BMME. In our recent studies of the NUP98-HOXD13 (NHD13) transgenic mouse model of MDS, transplantation of NHD13 marrow into the BMME of wild-type mice improved hematopoietic function, indicating that the MDS BMME is impaired in hematopoietic support and that this can be mitigated via bulk normalization to a healthy BMME. Moreover, NHD13 mice have abnormalities in BMME osteoblastic lineage cells and their mesenchymal stromal cell precursors, concurrent with decreased hematopoietic function. We find that these BMME changes are MDS-dependent derangements, in line with prior reports describing pathological ?reprogramming? of the BMME by neoplastic myeloid cells. Thus, we hypothesize that MDS cell-derived signals induce dysfunction in mesenchymal-osteolineage populations to impair the BMME?s ability to support normal hematopoietic function. A corollary to this is that hematopoietic failure in MDS can be mitigated by blocking interactions of MDS-cell initiated signals with BMME cells. The specific MDS-initiated signals and the BMME population they interact with are currently unknown. To test our hypothesis, we will define MDS-induced changes in BMME mesenchymal-osteolineage cells in vivo using the NHD13 model. We will also identify MDS-initiated signals that impair the BMME and determine if eliminating these signals can restore health to the MDS BMME and improve hematopoietic function in MDS. These studies will clarify the mechanism of BMME dysfunction in MDS and its role in hematopoietic failure to potentially identify therapeutic targets in the MDS BMME to recover hematopoietic function in patients with MDS.

Public Health Relevance

Myelodysplastic syndrome is (MDS) the most common myeloid malignancy in the United States that predominantly affects older adults, leading to bone marrow failure due to ineffective blood cell production. Because current MDS treatments MDS are inadequate, resulting in poor overall survival, and disease prevalence will likely increase with the growing aged population, there is a crucial need now to identify new MDS therapies. We propose to study the bone marrow microenvironment that normally supports hematopoiesis to understand how it is altered in MDS and how it may be targeted therapeutically to improve hematopoietic function in patients with MDS to enhance quality of life and survival.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30DK113727-01
Application #
9328257
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Roy, Cindy
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627