Abstract
BackgroundDespite 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.MethodsGSE13159 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.ResultsA 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.ConclusionThese 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.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, which is characterized by recurrent chromosomal and molecular abnormalities of immature lymphoid cells [1]
Previous studies demonstrated that the mixed-lineage leukemia (MLL) fusion proteins directly stimulated the histone methylation and target genes transcriptional elongation with the cooperation of DOT1L, PAFc, and pTEFb, leading to the persistent expression of genes that are important for the cell signaling, regulation of hematopoiesis, and transcription [11,12,13]
Our results provided the framework of co-expression gene modules of MLLr ALL, which would be beneficial to the clinical diagnosis and treatment of childhood MLL-r ALL
Summary
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, which is characterized by recurrent chromosomal and molecular abnormalities of immature lymphoid cells [1]. Despite the much improvement in treatment for ALL, childhood ALL with MLL-rearrangement (MLL-r) still displays inferior prognosis attributed to hyperleukocytosis, aggressive form with early relapse, and central nervous system involvement [4,5,6], distinguishing itself from other leukemia subgroups. MLL-r genes form fusions with more than 80 partner genes, of which the most common ones are AF4, AF9, ELL, and ENL [7]. MLL-AF4 fusion represents the largest subgroup and is associated with a particular poor prognosis [8]. Exploring novel genes and pathways associated with MLL-r ALL may help to identify potential molecular mechanisms, diagnostic markers, and therapeutic targets in this special subgroup. Despite much improvement in the treatment for acute lymphoblastic leukemia (ALL), childhood ALLs with MLL-rearrangement (MLL-r) still have inferior dismal prognosis. Defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy
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