# Role of MIF in myeloma bone homing and drug response

> **NIH NIH R01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2021 · $369,431

## Abstract

Project Summary
Multiple myeloma (MM), characterized by an accumulation of malignant plasma cells in the bone marrow (BM),
is the most common bone malignancy in the United States. Although chemotherapy is the most effective
treatment, the majority of patients experience relapse and die of the disease. The major cause of treatment
failure is the development of multidrug resistance. The BM microenvironment confers MM chemoresistance.
Deducing how the BM creates a microenvironment friendly to MM cells and confers resistance is thus the key
to overcoming drug resistance and greatly improving patient survival. Recently we discovered that human MM-
derived MIF (macrophage migration inhibitory factor) regulates the homing or affinity of MM cells for BM and,
as a result, their sensitivity to chemotherapy. MIF is highly expressed by human MM cells and the expression
levels positively correlate with advanced disease and poor survival in patients. Surprisingly, knocking down
MIF in MM cells impaired their adhesion to BM stromal cells (BMSCs) in vitro and led to formation of
extramedullary tumors in SCID mice. More importantly, MIF-knockdown human MM cells were more sensitive,
compared with control cells, to chemotherapy in SCID mice because chemotherapy effectively eradicated
extramedullary but not intramedullary tumors in the host. Inhibiting MIF activity in MM cells (cell lines and
primary MM cells from patients) by the MIF inhibitor (4-IPP) or neutralizing mAbs also resulted in impaired
adhesion to BMSCs in vitro and formation of extramedullary tumors in SCID and SCID-hu mice without
affecting tumor burdens. Furthermore, MM-(transwell)-conditioned human BMSCs mediated stronger adhesion
to MM cells, provided greater protection to MM cells against chemotherapy-induced apoptosis, and attracted
more monocytes than MIF-knockdown MM-conditioned BMSCs. Based on these novel findings, we
hypothesize that high MIF in MM cells contributes to poor patient survival by enhancing the affinity of MM cells
for BM and by conditioning BM to become a MM-friendly microenvironment, leading to enhanced MM growth
and survival and induction of drug resistance. Aim 1 will elucidate the mechanisms of MM-derived MIF in
regulating MM homing to and affinity for BM. Aim 2 will determine the importance and mechanisms of MM-
derived MIF in conditioning BM to become a MM-friendly microenvironment, and Aim 3 will determine and
validate the role of MM-expressing MIF in patients with MM. Accomplishing these aims will provide the
justification and tools for developing novel and effective strategies to target MIF to improve the therapeutic
efficacy of chemotherapy. The proposed studies will also lead to a better understanding of the fundamental
mechanisms underlying MM homing or metastasis to the bone and MM conditioning the microenvironment,
and could pave the way to the first substantial improvements in current MM treatment by mobilizing MM cells
away from the protective BM microenvironment...

## Key facts

- **NIH application ID:** 10078263
- **Project number:** 5R01CA211073-05
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** Qing Yi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,431
- **Award type:** 5
- **Project period:** 2017-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078263

## Citation

> US National Institutes of Health, RePORTER application 10078263, Role of MIF in myeloma bone homing and drug response (5R01CA211073-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10078263. Licensed CC0.

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