# Project 2: Investigating regulation of transcriptional condensates in multiple myeloma

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2024 · $353,763

## Abstract

Project Summary – Project 2 Whitehead Institute at MIT
There have been substantial advances in our understanding of the transcriptional control of cell states and how
they are dysregulated in tumor cells. While investigating the transcriptional and epigenetic regulation of multiple
myeloma (MM) cells in the previous funding period, our studies led to a new model for transcriptional control of
cell state, one where the transcriptional and epigenetic apparatus becomes compartmentalized in biomolecular
condensates and is regulated by biomolecules in a manner not anticipated by the canonical models of gene
regulation (Figure 1). We discovered that the super-enhancers that drive oncogenes form large condensates
that compartmentalize master transcription factors (TFs), epigenetic apparatus, regulatory RNA molecules and
large numbers of RNA polymerase molecules to enable high rates of oncogene transcription. Furthermore, we
found that newly transcribed RNA molecules make a profound contribution to local gene regulation both by
directly binding to TFs and by altering the lifetime of the super-enhancer condensates. Importantly, we also
discovered that these transcriptional condensates have chemical properties that concentrate the tested
antineoplastic drugs over a hundred-fold, such that the pharmacological properties of the drug are altered in the
vicinity of the drug’s target. Further insights into condensate physicochemistry should enable development of
therapeutic molecules with improved efficacy and reduced toxicity. Based on these studies we propose to
advance our understanding, in MM cells, of the regulation of transcriptional condensates and the biochemical
environment in these condensates that influences drug behavior. To achieve these goals, the following Aims will
be pursued: 1) To investigate the role of RNA binding by master transcription factors in MM cell state, 2) To
investigate the role of RNA in regulation of oncogenic transcriptional condensates and DNA damage repair
condensates in MM, and 3) To investigate the features of condensate chemistry that provide a specific chemical
environment for enhancer-associated apparatus and that concentrate antineoplastic drugs. These proposed
studies will advance our understanding of the regulation of transcriptional condensates and the biochemical
environment in these condensates, and may thus enable development of novel therapeutic molecules with
improved efficacy and reduced toxicity.

## Key facts

- **NIH application ID:** 10894594
- **Project number:** 5P01CA155258-12
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** RICHARD YOUNG
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $353,763
- **Award type:** 5
- **Project period:** 2011-12-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894594

## Citation

> US National Institutes of Health, RePORTER application 10894594, Project 2: Investigating regulation of transcriptional condensates in multiple myeloma (5P01CA155258-12). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10894594. Licensed CC0.

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