# Molecular Manipulation to Enhance Anti-Myeloma Response

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2024 · —

## Abstract

Multiple myeloma (MM) is a heterogenous disease. Although there have been several novel agents
and combinations available for treatment, the genomic adaptability of the tumor cells lead to their
continued growth and and adverse survival outcome. Therefore there is need for identification of novel
target sand directed therapies. One of the emrging areas of research in this direction has been the
recent advances highlighting the functional significance of long noncoding RNAs (lncRNAs) that span
> 80% of human genome. These RNA molecules control variety of cellular and molecular functions via
mechanisms that are as yet not well described. In our preliminary investigation we utilized our RNA-
seq data from CD138+ MM cells from 308 newly diagnosed and uniformly treated patients, and 16
normal plasma cells and described the aberrant lncRNA landscape in MM. We identified 869
differentially expressed lncRNAs in MM compared to normal plasma cells. We identified 14 lncRNAs
associated with PFS and calculated a risk score that stratified patients and report their significant role
as an independent risk predictor for clinical outcome1. These results provided the rationale to further
investigate biological and molecular activity of lncRNA in MM. We evaluated 913 expressed lncRNAs
for impact on MM cell viability in a preliminary CRISPR interference (CRISPRi)-based screen. A primary
screen in 3 MM cell lines identified 20 lncRNAs impacting MM cell viability. Evaluation using RNA-seq
data showed a significant upregulation of these 20 lncRNAs. Of note, specific lncRNAs were found
selectively upregulated in genetically-defined patient subsets, including high-risk MM carrying t(4;14).
A secondary screen (of the most enriched or depleted sgRNAs) identified MIR17HG (RNA Regulator
of Lipogenesis; RROL), as one of the top hits as a novel lncRNA in MM. In subsequent experiments,
suppression of RROL significantly impaired MM cell growth and survival in vitro and in vivo. We also
observed that Acetyl Co-A Carboxylase 1 (ACC1), the rate-limiting enzyme of de novo lipogenesis
(DNL) pathway, is one of the primary targets of RROL. This metabolic pathway converts nutrients
(glucose, glutamine, etc.) into fatty acids serving for energy storage or biosynthesis of membranes and
signaling molecules. We have also begun to investigate inhibitors of both lncRNA RROL as well as
ACC1 and observed anti-MM activity. Based on these observations, we hypothesize that dysregulated
lncRNAs significantly impact the pathobiology of MM by their ability to control multiple genes, with
potential to serve as therapeutic targets. To further understand the role of lncRNAs in MM and identify
those associated with progression, and to evaluate their therapeutic potential, we will identify functional
lncRNA dependencies in myeloma (Aim 1), validate the role of functional lncRNAs in MM (Aim 2) and
evaluate inhibitors of MIR17HG (RROL) and its downstream target using small molecule and transgenic
manipulati...

## Key facts

- **NIH application ID:** 10765654
- **Project number:** 5I01BX001584-10
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** Nikhil C. Munshi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765654

## Citation

> US National Institutes of Health, RePORTER application 10765654, Molecular Manipulation to Enhance Anti-Myeloma Response (5I01BX001584-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10765654. Licensed CC0.

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