Lenalidomide is a highly effective treatment for patients with myelodysplastic syndrome (MDS) with deletion of Chromosome 5q (del(5q)), with approximately 50% of patients achieving a complete cytogenetic response. In the previous funding period, we determined the mechanistic basis for the therapeutic efficacy of lenalidomide in del(5q) MDS, generated the first murine model that responds to lenalidomide, and developed a quantitative mass spectrometry-based approach to evaluate the activity of lenalidomide and related molecules. We now propose to investigate the molecular basis for incomplete responses to lenalidomide and acquired resistance, and to develop a novel therapeutic approach that bypasses resistance. First, we aim to determine mechanisms of sensitivity and resistance that have not been previously investigated: the impact of lenalidomide on stem cells, the bone marrow microenvironment, and the immune system. These experiments are enabled by the CRBNI391V murine model, developed during the previous funding period, that is sensitive to lenalidomide. Next, we will examine combinatorial targeting of CSNK1A1 and GSPT1 with a new thalidomide derivative, CC-885, and investigate the mechanism of GSPT1-mediated cytotoxicity in models of del(5q) MDS. Finally, we will investigate the biochemistry of lenalidomide-dependent degradation of oncoproteins by the CRL4CRBN E3 ubiquitin ligase, validating genes identified through genome-wide CRISPR screens. These studies will inform the biology of thalidomide derivatives in general, provide a comprehensive description and mechanistic understanding of thalidomide derivative effects on immune system homeostasis, and contribute to the development of novel therapeutics for del(5q) MDS.

Public Health Relevance

Myelodysplastic syndrome (MDS) is a disease of abnormal blood production that frequently progresses to acute leukemia. Heterozygous deletion of chromosome 5q is the most common chromosomal abnormality in MDS. We aim to develop novel therapies for MDS patients with this genetic lesion and to understand mechanisms of drug resistance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL082945-13
Application #
9738040
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Di Fronzo, Nancy L
Project Start
2005-09-15
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
13
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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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
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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

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