# Targeting IRE-1a/XBP-1 Axis for Control of Chronic GVHD and Leukemia Relapse

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $72,779

## Abstract

Abstract
Hematological malignancies that include leukemia and lymphoma are often treated with allogeneic
hematopoietic stem cell transplantation (allo-HCT). However, chronic graft-versus-host disease (cGVHD)
remains a prominent cause of transplant-related morbidity and mortality despite available immunosuppressive
regimens. Few prophylactic strategies have been successful at reducing the incidence of cGVHD in patients
after allo-HCT. An area previously unexplored as a treatment for cGVHD involves the unfolded protein
response (UPR). Three master regulators control the UPR: PERK, IRE-1α, and ATF6. When IRE-1α becomes
activated, its primary function is to splice Xbox binding protein-1 (XBP-1u) mRNA. Spliced XBP-1 (XBP-1s)
mRNA is translated into XBP-1 protein which acts as an effective nuclear transcription factor. Immune
responses such as B-cell proliferation and antibody production require large amounts of properly folded
proteins. As a transcription factor, XBP-1 protein relieves ER stress by up regulating cellular machinery
responsible for protein folding and degradation. XBP-1 is therefore required for the effector function and
survival of various types of immune cells that are susceptible to ER stress. IRE-1α/XBP-1 signaling axis plays
predominate roles in B cells and dendritic cells (DCs) among other immune cells. Built upon published findings
and our preliminary observations, we will evaluate how IRE-1α/XBP-1 signaling axis impacts in the
development of cGVHD after allo-HCT through regulating B cells and DCs among others. Our Central
Hypothesis is that XBP-1 plays an essential role for B-cell and DC activation and function, and targeting XBP-1
will restrain allogeneic responses leading to the control of cGVHD while preserving the integrity of cytotoxic T
lymphocytes (CTL) and thus maintaining the graft-versus-leukemia (GVL) effect. This hypothesis will be tested
in the following two Specific Aims: 1) Define the contribution of XBP-1 on hematopoietic cells in the
development of cGVHD after allo-HCT using a genetic approach; 2) Determine the therapeutic effect of
targeting XBP-1 in the control of cGVHD and leukemia relapse using a pharmacological approach. The current
study is expected to further understand the cell biology how UPR regulates immune responses, reveal the role
for IRE-1α/XBP-1 signaling axis in the development of cGVHD and relatable hematologic malignancies, and
provide a novel therapy for controlling cGVHD and leukemia relapse in after allo-HCT.

## Key facts

- **NIH application ID:** 10179448
- **Project number:** 5R01HL140953-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Xue-Zhong Yu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $72,779
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-01-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179448

## Citation

> US National Institutes of Health, RePORTER application 10179448, Targeting IRE-1a/XBP-1 Axis for Control of Chronic GVHD and Leukemia Relapse (5R01HL140953-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10179448. Licensed CC0.

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