# Functional  Genomic  Dissection  of  Refractory  Anemia

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2022 · $441,250

## Abstract

ABSTRACT
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.

## Key facts

- **NIH application ID:** 10428537
- **Project number:** 5R01HL082945-16
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Benjamin Levine Ebert
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $441,250
- **Award type:** 5
- **Project period:** 2005-09-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428537

## Citation

> US National Institutes of Health, RePORTER application 10428537, Functional  Genomic  Dissection  of  Refractory  Anemia (5R01HL082945-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10428537. Licensed CC0.

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