Abstract
The pathways and robust deregulated gene signatures involved in AML chemo-resistance are not fully understood. Multiple subgroups of AMLs which are under treatment of various regimens seem to have similar regulatory gene(s) or pathway(s) related to their chemo-resistance phenotype. In this study using gene set enrichment approach, deregulated genes and pathways associated with relapse after chemotherapy were investigated in AML samples. Five AML libraries compiled from GEO and ArrayExpress repositories were used to identify significantly differentially expressed genes between chemo-resistance and chemo-sensitive groups. Functional and pathway enrichment analysis of differentially expressed genes was performed to assess molecular mechanisms related to AML chemotherapeutic resistance. A total of 34 genes selected to be differentially expressed in the chemo-resistance compared to the chemo-sensitive group. Among the genes selected, c-Jun, AKT3, ARAP3, GABBR1, PELI2 and SORT1 are involved in neurotrophin, estrogen, cAMP and Toll-like receptor signaling pathways. All these pathways are located upstream and regulate JNK signaling pathway which functions as a key regulator of cellular apoptosis. Our expression data are in favor of suppression of JNK pathway, which could induce pro-apoptotic gene expression as well as down regulation of survival factors, introducing this pathway as a key regulator of drug-resistance development in AML.
Highlights
Acute myeloid leukemia (AML) is one of the most aggressive, life-threatening hematological malignancies characterized by uncontrolled proliferation of abnormal differentiated and nonfunctional myeloid precursor cells[1]
The datasets were as following: (1) GSE52919 involved a gene expression profiling of patients with AML receiving chemotherapy with cytarabine (Ara-C) and daunorubicin (DNR) gene expression. The participants of this microarray dataset were adult with the age of 18–61 years with median age of 39 years, (2) GSE52891 contained expression profiling associated with pediatric relapsed AML patients with median age of 13.2 after receiving cytarabine and anthracycline as an initial therapy, (3) GSE75086 consisted of RNA expression profiling of samples with AraC-based chemotherapy at post induction, relapse and diagnostic sample (Of these, the relapsed samples were used), (4) GSE107465 encompassed expression profiling of 30 different AML patients who received different chemotherapy protocols
In this study we wished to investigate deregulated genes and enriched pathways involved in drug resistance in AML patients under treatment of DNA-damaging agents including Anthracyclines, Cytarabine and Gemtuzumab ozogamicin
Summary
Acute myeloid leukemia (AML) is one of the most aggressive, life-threatening hematological malignancies characterized by uncontrolled proliferation of abnormal differentiated and nonfunctional myeloid precursor cells[1]. Some of the clinicians intensify induction therapy by adding an anthracycline or other therapeutic compounds to enhance the likelihood of achieving a complete remission (CR)[6] These alterations in the standard frontline therapy include use of different types of anthracyclines, mainly daunorubicin, idarubicin and etoposide as well as different cytotoxic agents such as topoisomerase II inhibitors (mitoxantrone), nucleoside analogues (azacitidine) and gemtuzumab ozogamicin (GO; a CD33-directed antibody-drug conjugate) which are added to induction therapy with or without cytokines and differentiation agents[4,6,7]. Functional and pathway enrichment analysis of DEGs were performed to provide deeper understanding of molecular mechanism of DNA damaging-induced chemotherapy resistance
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