# Core transcriptional regulators of malignant stem cell generation in multiple myeloma

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $361,425

## Abstract

ABSTRACT
Multiple myeloma is a fatal plasma cell neoplasm that is characterized by the malignant expansion of abnormal
antibody-producing cells. Despite recent therapeutic advances, most patients eventually relapse. Such high-
risk patients typically have an overall survival rate of less than one year. These poor clinical outcomes occur as
a result of uncontrolled regeneration of malignant stem-like cells in protective, inflammatory
microenvironments. However, the precise transcriptional determinants of myeloma stemness in the bone
marrow niche remain poorly understood. One intriguing candidate is a key B-cell transcription factor and
myeloma cell survival factor, interferon response factor-4 (IRF4). IRF4 also governs normal plasma cell
development and immune responses to inflammation, however the extent to which IRF4 promotes malignant
progenitor generation in lymphoid or plasma cell neoplasms is unknown. A 50% reduction in IRF4 expression
can disrupt myeloma cell survival, but IRF4 remains undeveloped as a therapeutic target because transcription
factors are difficult to inhibit using traditional small molecule strategies. To overcome this challenge, proof-of-
concept studies were performed to evaluate novel RNA-targeted therapeutic agents that directly inhibit human
IRF4 RNA expression and protein translation. Based on extensive preliminary data that characterized IRF4
expression and activity in clinically-relevant in vitro and in vivo models, the central hypothesis of this project is
that inhibition of IRF4 will disrupt stem cell pathway activation in multiple myeloma and synergize with
standard-of-care drugs to reduce overall disease burden and prevent malignant stem cell generation. In the
context of three independent yet conceptually interrelated aims, this hypothesis will be tested in
comprehensive molecular and cellular assays through a rigorous scientific approach. Aim 1: Interrogating the
role of IRF4 in functional myeloma stem cell generation. This aim will determine the cell-intrinsic mechanisms
that link IRF4 to myeloma regeneration. Aim 2: IRF4 inhibitor monotherapy and combination drug treatment in
pre-clinical models of multiple myeloma. This aim will develop combination drug treatment and biomarker
detection strategies that leverage selective IRF4 inhibition. Aim 3: Elucidating the bone marrow
microenvironment-derived signals that promote IRF4 pathway activation in myeloma regeneration. This aim will
elucidate the paracrine mechanisms underlying myeloma regeneration and the activity of a novel cancer
therapeutic. The proposed research will set the stage for rapid clinical translation of more selective
combination therapies for myeloma. The research team unites cancer and stem cell biology experts, myeloma
clinicians, and collaborators who are highly experienced in the translation of novel therapeutics for cancer.
Together, this project is positioned to advance the rapid clinical translation of IRF4 inhibitor therapy for
myeloma....

## Key facts

- **NIH application ID:** 10489708
- **Project number:** 5R37CA252040-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Leslie A Crews
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $361,425
- **Award type:** 5
- **Project period:** 2021-09-16 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10489708

## Citation

> US National Institutes of Health, RePORTER application 10489708, Core transcriptional regulators of malignant stem cell generation in multiple myeloma (5R37CA252040-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10489708. Licensed CC0.

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