Myelodysplastic syndrome (MDS) has been long recognized as a collection of diseases characterized by ineffective hematopoiesis associated with impairment of differentiation and intra-medullary apoptosis. Moreover, patients with MDS often progress to acute myeloid leukemia (AML). The pathogenesis of MDS remains obscure, and effective therapies are lacking. One challenge is that MDS represents a diverse collection of diseases, categorized by often vague clinical criteria. One exception to this, however, is the 5q syndrome, which has distinct clinical characteristics and is associated with deletions of the long arm of chromosome 5. The disease gene for this syndrome has yet to be identified. We therefore propose here an ambitious genomics-based approach to the cloning of the 5q- syndrome disease gene, and to the discovery of small molecules that circumvent the differentiation block that is characteristic of MDS.
In Aim 1, we will perform a systematic, RNA interference-based functional genomic screen in CD34+ primary hematopoietic progenitor cells to identify those genes in the critically deleted region of 5q that recapitulate the differentiation defect characteristic of MDS. In addition, we will perform fine-mapping of the 5q region using high density custom microarray comparative genomic hybridization (CGH) in order to identify patients with previously unrecognized, small deletions. Furthermore, we will utilize .a novel single-molecule sequencing method to resequence the candidate genes on 5q for mutations.
In Aim 2, we will perform a high throughput gene expression-based small molecule screen using the GE-HTS method developed in our laboratory. Using this approach, we expect to identify small molecules (or drugs) capable of promoting the expansion and differentiation of hematopoietic progenitors. Such compounds would be valuable both as tool compounds with which to dissect the biology of MDS, and as potential starting points for the development of new therapies of MDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082945-04
Application #
7459616
Study Section
Special Emphasis Panel (ZHL1-CSR-I (S1))
Program Officer
Di Fronzo, Nancy L
Project Start
2005-09-15
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$430,154
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Sievers, Quinlan L; Gasser, Jessica A; Cowley, Glenn S et al. (2018) Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 132:1293-1303
Sievers, Quinlan L; Petzold, Georg; Bunker, Richard D et al. (2018) Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362:
Fink, Emma C; McConkey, Marie; Adams, Dylan N et al. (2018) CrbnI391V is sufficient to confer in vivo sensitivity to thalidomide and its derivatives in mice. Blood 132:1535-1544
Kahn, Josephine D; Miller, Peter G; Silver, Alexander J et al. (2018) PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells. Blood 132:1095-1105
Li, Hubo; Mar, Brenton G; Zhang, Huadi et al. (2017) The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia. Blood 129:497-508
Kennedy, James A; Ebert, Benjamin L (2017) Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome. J Clin Oncol 35:968-974
Jan, Max; Ebert, Benjamin L; Jaiswal, Siddhartha (2017) Clonal hematopoiesis. Semin Hematol 54:43-50
Tothova, Zuzana; Krill-Burger, John M; Popova, Katerina D et al. (2017) Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia. Cell Stem Cell 21:547-555.e8
Jaiswal, Siddhartha; Natarajan, Pradeep; Silver, Alexander J et al. (2017) Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med 377:111-121
Lindsley, R Coleman; Saber, Wael; Mar, Brenton G et al. (2017) Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med 376:536-547

Showing the most recent 10 out of 56 publications