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High Expression of BCL11A Predicts Poor Prognosis for Childhood MLL-r ALL
Lu-Lu Wang1, Dehong Yan2, Xue Tang1
1Department of Hematology and Oncology, Shenzhen Children's Hospital, Shenzhen, China.
Insights
Childhood acute lymphoblastic leukemia with MLL-rearrangement (MLL-r ALL) has a poor prognosis. Upregulated BCL11A expression in MLL-r ALL suggests it is a potential therapeutic target for this aggressive leukemia.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Childhood acute lymphoblastic leukemia (ALL) with MLL-rearrangement (MLL-r) presents a dismal prognosis despite treatment advancements.
- Understanding the mechanisms driving MLL-r ALL is crucial for developing effective therapies.
Purpose of the Study:
- To identify key genes and pathways involved in the development and maintenance of MLL-r ALL.
- To explore potential therapeutic targets for childhood MLL-r ALL.
Main Methods:
- Differential gene expression analysis (DEGs) using Oncomine datasets (GSE13159, GSE28497).
- Functional enrichment analysis (GO, KEGG, GSEA, STRING) and Weighted Gene Co-expression Network Analysis (WGCNA).
- Validation of key genes through UCSC Xena, qPCR, and Kaplan-Meier survival analysis in patient samples and cell lines.
Main Results:
- Identified 1,045 DEGs, with upregulation in "nucleosome assembly" and "B cell receptor signal pathway" in MLL-r ALL.
- WGCNA identified 18 hub genes, with 9 correlated to MLL-r status. Three genes (BCL11A, GLT8D1, NCBP2) were elevated in MLL-r ALL patient bone marrow.
- High BCL11A expression correlated with significantly poorer overall survival in childhood ALL patients.
Conclusions:
- Upregulated BCL11A expression is implicated in the development of childhood MLL-r ALL.
- BCL11A represents a promising novel therapeutic target for childhood MLL-r ALL.
Background:
Despite much improvement in the treatment for acute lymphoblastic leukemia (ALL), childhood ALLs with MLL-rearrangement (MLL-r) still have inferior dismal prognosis. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy.
Methods:
GSE13159 and GSE28497 were selected via the Oncomine website. Differentially expressed genes (DEGs) between MLL-r ALLs and normal samples were identified by R software. Next, functional enrichment analysis of these DEGs were carried out by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Then, the key hub genes and modules were identified by Weighted Gene Co-expression Network Analysis (WGCNA). Therapeutically Applicable Research to Generate Effective Treatments (TARGET) ALL (Phase I) of UCSC Xena analysis, qPCR, and Kaplan-Meier analysis were conducted for validating the expression of key hub genes from bone marrow cells of childhood ALL patients or ALL cell lines.
Results:
A total of 1,045 DEGs were identified from GSE13159 and GSE28497. Through GO, KEGG, GSEA, and STRING analysis, we demonstrated that MLL-r ALLs were upregulating "nucleosome assembly" and "B cell receptor signal pathway" genes or proteins. WGCNA analysis found 18 gene modules using hierarchical clustering between MLL-r ALLs and normal. The Venn diagram was used to filter the 98 hub genes found in the key module with the 1,045 DEGs. We identified 18 hub genes from this process, 9 of which were found to be correlated with MLL-r status, using the UCSC Xena analysis. By using qPCR, we validated these 9 hub key genes to be upregulated in the MLL-r ALLs (RS4;11 and SEM) compared to the non-MLL-r ALL (RCH-ACV) cell lines. Three of these genes, BCL11A, GLT8D1 and NCBP2, were shown to be increased in MLL-r ALL patient bone marrows compared to the non-MLL-r ALL patient. Finally, Kaplan-Meier analysis indicated that childhood ALL patients with high BCL11A expression had significantly poor overall survival.
Conclusion:
These findings suggest that upregulated BCL11A gene expression in childhood ALLs may lead to MLL-r ALL development and BCL11A represents a new potential therapeutic target for childhood MLL-r ALL.
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