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Updated: May 1, 2026
Use of Hematopoietic Stem Cell Transplantation to Assess the Origin of Myelodysplastic Syndrome
Published on: October 3, 2018
Combined meta-analysis of systemic effects of allogeneic stem cell transplantation and systemic sclerosis
Dmitry N Grigoryev1, Jignesh Dalal, Mara L Becker
1Division of Experimental and Translational Genetics, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO, USA. dgrigoryev@cmh.edu.
Insights
This study combined chronic graft-versus-host disease (cGVHD) and systemic sclerosis (SSc) data to find new molecular targets. The novel meta-analysis approach identified key genes linking these diseases, offering potential therapeutic insights.
Area of Science:
- Immunology
- Genomics
- Transplantation medicine
Background:
- Chronic graft-versus-host disease (cGVHD) is a significant complication of allogeneic stem cell transplantation (aSCT).
- cGVHD shares clinical and immunological similarities with systemic sclerosis (SSc), particularly in skin and internal organ involvement.
- Both conditions involve circulating lymphocytes, suggesting common underlying autoimmune mechanisms.
Purpose of the Study:
- To develop a novel meta-analysis approach combining data from cGVHD and SSc.
- To identify novel molecular targets associated with the systemic effects of cGVHD and SSc.
- To leverage shared clinical manifestations for enhanced data analysis.
Main Methods:
- Data from aSCT and SSc microarray studies were integrated from the Gene Expression Omnibus (GEO).
- Expression genome-wide association studies (eGWAS) were performed on lymphocyte profiles.
- Gene signatures were analyzed using subtraction methods and pathway analysis to identify common and novel candidates.
Main Results:
- The meta-analysis identified 35 candidate genes, including 8 known cGVHD genes and 28 novel candidates.
- Pathway analysis highlighted 7 genes in the fibroblast development and function pathway, including known genes (CCND1, JUN, FOS) and new targets (MMP2, FOSB, TNFAIP8, DUSP1).
- These identified genes are potential links between the systemic effects of cGVHD and SSc.
Conclusions:
- A novel meta-analysis method was developed by linking diseases with common clinical manifestations.
- This approach successfully enhanced the analysis of limited aSCT microarray data by incorporating SSc data.
- The study identified novel molecular targets for systemic cGVHD and SSc, demonstrating the generalizability of the method for other related diseases.
Background:
Chronic graft-versus-host disease (cGVHD) is a major factor of morbidity and mortality for allogeneic stem cell transplantation (aSCT). The skin and internal organ involvement is the most common systemic complication of cGVHD and closely resembles systemic sclerosis (SSc). Circulating lymphocytes characterize the autoimmune nature of both conditions. Therefore we hypothesized that the common clinical manifestation (systemic organ and skin injury) and the common underlying players (lymphocytes) justify the combined meta-analysis of these diseases.
Results:
The aSCT and SSc datasets were uploaded from Gene Expression Omnibus (GEO), a public functional genomics data repository. The available microarray studies of peripheral blood mononuclear cells (PBMCs) and isolated lymphocytes were limited to well established microarray platforms (Affymetrix, Agilent, Canvac, and Illumina) and experimental settings with ≥10 patients per group. The resulting pools of data were merged by unique gene identifier and analyzed by the expression genome-wide association studies (eGWAS) coupled with the subtraction of the cGVHD+ and cGVHD- molecular signatures. The eGWAS was applied to 47 and 50 lymphocyte profiles from aSCT and SSc patients, respectively. The identified 35 candidates were represented by 8 known cGVHD genes (including CXCR4, LTBR and PML) and 28 new candidate genes (including SEPX1 and DNJGB1). The further mutual subtraction of cGVHD+ and cGVHD- candidates and pathway analysis identified a list of 25 genes. Seven of these genes belong to the fibroblast development and function pathway, consisting of the well known cGVHD genes CCND1, JUN, and FOS, and the new molecular targets MMP2, FOSB, TNFAIP8, and DUSP1. These genes become primary candidates for a potential link of systemic effects of cGVHD and SSc.
Conclusions:
We designed a new approach for meta-analysis by combining data from different diseases using common clinical manifestation as a linker. This allowed us to power up the insufficient standalone meta-analysis of aSCT microarray studies, by adding SSc samples to the data pool. This new method has successfully identified novel molecular targets for systemic effects of both aSCT and SSc. We believe that this approach is generalizable and can be applied to an array of diseases with common clinical manifestations.
