# Analyzing protein homeostasis pathways in multiple myeloma stem-like cells

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $370,500

## Abstract

Abstract:
Multiple myeloma (MM) is an incurable B cell malignancy that is characterized by the growth of neoplastic
plasma cells within the bone marrow microenvironment. Despite progress in the clinical treatment of MM,
including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable
proportion of patients develop resistance and become refractory to therapies. Drug resistance in MM is
enabled by evolving genomic alterations as well as by contributions from stromal components in the bone
marrow microenvironment. Specifically, the bone marrow provides a protective niche for slowly cycling/
quiescent stem-like MM cells that are not killed by chemotherapies. We have discovered sub-populations of
MM stem-like cells that preferentially localize to osteoblastic niches of the bone marrow. Gene expression
profiling revealed that a novel tripartite motif factor, TRIM44, is upregulated in MM stem-like cells isolated from
the osteoblastic niche. TRIM family proteins function as autophagy-regulatory receptors and TRIM44 gene
silencing decreases autophagy. In this project, we will investigate roles for TRIM44 and its links to protein
homeostasis control during MM initiation, progression and resistance to therapy. Our working hypothesis is that
TRIM44 plays integral roles in promoting quiescent MM stem cell survival within the bone marrow niche by
regulating pathways involved in proteotoxic stress. Furthermore, we propose that targeting TRIM44 or its
interacting proteins will result in diminished MM survival and improved outcome in response to therapy. To test
this hypothesis, we will (i) analyze signaling pathways regulated by TRIM44 and determine how components of
these pathways promote cell survival under proteotoxic stress; (ii) characterize novel substrates (from a recent
mass spectrometry screen) that selectively bind to TRIM44 and determine the functional significance of these
interactions in primary MM cells; and (iii) delineate the clinical relevance of these TRIM44-dependent pathways
in MM pathogenesis and relapse using xenograft mouse models. Our long-term goal is to selectively inhibit
TRIM44-dependent signaling pathways to benefit patients by reducing MM progression and/or blocking tumor
recurrence after therapy.

## Key facts

- **NIH application ID:** 10111793
- **Project number:** 2R01CA181319-06A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Nami McCarty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $370,500
- **Award type:** 2
- **Project period:** 2014-07-02 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10111793

## Citation

> US National Institutes of Health, RePORTER application 10111793, Analyzing protein homeostasis pathways in multiple myeloma stem-like cells (2R01CA181319-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10111793. Licensed CC0.

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