Abstract
Rearrangements involving the mixed lineage leukemia (MLL) gene are common adverse prognostic factors of pediatric acute lymphoblastic leukemia (ALL). Even allogeneic hematopoietic stem cell transplantation does not improve the outcome of ALL cases with some types of MLL rearrangements. The aim of the present study was to identify the co-expressed genes that related to MLL rearrangement (MLL-r) and elucidate the potential mechanisms of how MLL-r and their partner genes lead to leukemogenesis. Gene co-expression networks were constructed using the gene expression data and sample traits of 204 pretreated pediatric ALL patients, and co-expression modules significantly related to the MLL-r were screened out. Gene ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway analysis of the module genes were performed. Hub genes were identified and their expression levels were analyzed in samples with or without MLL-r and the results were validated by an independent investigation. Furthermore, the relationships between the hub genes and sample traits were analyzed. In total, 21 co-expression modules were identified. The green module was positively correlated with MLL-r. PROM1, LGALS1, CD44, FUT4 and HOXA10 were identified as hub genes, which were involved in focal adhesion, calcium-dependent phospholipid binding, connective tissue development and transcriptional misregulation in cancer. The expression levels of the five hub genes were significantly increased in MLL-r samples, and the results were further validated. PROM1, LGALS1, CD44 and HOXA10 were positively related to the leukocyte count. These findings might provide novel insight regarding the mechanisms and potential therapeutic targets for pediatric ALL with MLL-r.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children [1]
The aim of the present study is to investigate the genes significantly related to mixed lineage leukemia (MLL)-r ALL and elucidate the mechanisms of how MLL fusions and their partner genes lead to leukemogenesis, which may provide novel therapeutic targets for ALL with MLL gene rearrangement (MLL-r)
It remains challenging to elucidate the molecular mechanisms of MLL-r leukemia and identify new therapeutic targets
Summary
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among children [1]. 98% of patients with pediatric ALL achieve remission, and 85% of patients aged 1–18 years with newly diagnosed ALL treated on current regimens are expected to be long-term event-free survivors, with over 90% surviving at 5 years [2,3]. Several high-risk cytogenetic and molecular subtypes of ALL are associated with unfavorable outcomes. Rearrangements involving the mixed lineage leukemia (MLL) gene ( known as the KMT2A gene), which occur in approximately 5–10% of overall childhood ALL cases, are common adverse prognostic factors of ALL [6,7]. MLL gene rearrangement (MLL-r) is significantly associated with high risks of treatment failure, relapse and CNS involvement [8]. The 5-year event-free survival (EFS) and overall survival (OS) rates of these patients are worse than those of patients without MLL rearrangement (non-MLL-r).
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