Abstract
Infant acute lymphoblastic leukemia (ALL) with the mixed lineage leukemia (MLL) gene rearrangement (MLL-R) is considered a distinct leukemia from childhood or non-MLL-R infant ALL. To detect key genes and elucidate the molecular mechanisms of MLL-R infant ALL, microarray expression data were downloaded from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between MLL-R and non-MLL-R infant ALL were identified. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were carried out. Then, we constructed a protein-protein interaction (PPI) network and identified the hub genes. Finally, drug-gene interactions were mined. A total of 139 cases of MLL-R infant ALL including 77 (55.4%) fusions with AF4, 38 (27.3%) with ENL, 14 (10.1%) with AF9, and 10 (7.2%) other gene fusions were characterized. A total of 236 up-regulated and 84 down-regulated DEGs were identified. The up-regulated DEGs were mainly involved in homophilic cell adhesion, negative regulation of apoptotic process and cellular response to drug GO terms, while down-regulated DEGs were mainly enriched in extracellular matrix organization, protein kinase C signaling and neuron projection extension GO terms. The up-regulated DEGs were enriched in seven KEGG pathways, mainly involving transcriptional regulation and signaling pathways, and down-regulated DEGs were involved in three main KEGG pathways including Alzheimer’s disease, TGF-beta signaling pathway, and hematopoietic cell lineage. The PPI network included 297 nodes and 410 edges, with MYC, ALB, CD44, PTPRC and TNF identified as hub genes. Twenty-three drug-gene interactions including four up-regulated hub genes and 24 drugs were constructed by Drug Gene Interaction database (DGIdb). In conclusion, MYC, ALB, CD44, PTPRC and TNF may be potential bio-markers for the diagnosis and therapy of MLL-R infant ALL.
Highlights
Infant acute lymphoblastic leukemia (ALL) refers to ALL arising in infants prior to 12 months of age
We investigated the molecular mechanisms of mixed lineage leukemia (MLL)-R infant ALL by determining differentially expressed genes (DEGs) between MLL rearrangements (MLL-R) and non-MLL-R infant ALL, using available microarray datasets, followed by bio-functional enrichment of identified DEGs
DEGs between MLL-R and non-MLL-R infant ALL cases were identified using the Bayesian method by Limma package in R (Ritchie et al, 2015). |log2 fold change (FC)|>1 and a P value
Summary
Infant acute lymphoblastic leukemia (ALL) refers to ALL arising in infants prior to 12 months of age. Identification of hub genes and molecular mechanisms in infant acute lymphoblastic leukemia with MLL gene rearrangement. 80% of infant ALL cases are characterized genetically by rearrangements in the mixed lineage leukemia gene (MLL, known as KMT2A, located on chromosome 11q23) (Krivtsov & Armstrong, 2007). These rearrangements occur in nearly 100% of infants with congenital leukemia and approximately 5% of pediatric ALL patients, with predicted inferior outcomes (Van der Linden et al, 2009). Novel treatment targets and molecular-targeted strategies are required to improve outcomes of infant ALL patients with MLL-R
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