Transcriptomic analysis delineates potential regulatory network as therapeutic alternatives in chronic myeloid leukemia

Abstract Background Chronic myeloid leukemia (CML) relapse and progression after discontinuation of tyrosine kinase inhibitors (TKI) therapy in the chronic phase (CP) are attributed to primitive quiescent leukemic progenitor cells (LPCs). This study aimed to identify key differentially expressed genes (DEGs) involved in molecular pathways alternative to BCR-ABL, which could lead to the eradication of leukemic stem/progenitor cells. Methods mRNA expression profiling dataset comprising newly diagnosed untreated CP CML leukemic progenitor cell samples $$\left( {n = 5} \right)$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mfenced> <mml:mrow> <mml:mi>n</mml:mi> <mml:mo>=</mml:mo> <mml:mn>5</mml:mn> </mml:mrow> </mml:mfenced> </mml:math> and normal hematopoietic progenitor cell samples $$\left( {n = 5} \right)$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mfenced> <mml:mrow> <mml:mi>n</mml:mi> <mml:mo>=</mml:mo> <mml:mn>5</mml:mn> </mml:mrow> </mml:mfenced> </mml:math> were selected for DEGs identification. A weighted gene co-expression network was constructed to identify significant hub modules. Protein–protein interaction (PPI) network construction and pathway enrichment analysis provided additional information on the biological pathways involved. The genes involved in the resultant PPI network were subjected to a gene transcriptional regulatory network based on transcription factors (TFs) and microRNAs (miRNAs) involved in the target genes. Results A total of 709 genes that were differentially expressed among those corresponding to $$p &lt; 0.05$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>p</mml:mi> <mml:mo>&lt;</mml:mo> <mml:mn>0.05</mml:mn> </mml:mrow> </mml:math> and $$\left| {\log_{2} \left( {FC} \right)} \right| &gt; 0.5$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mfenced> <mml:mrow> <mml:msub> <mml:mo>log</mml:mo> <mml:mn>2</mml:mn> </mml:msub> <mml:mfenced> <mml:mrow> <mml:mi>FC</mml:mi> </mml:mrow> </mml:mfenced> </mml:mrow> </mml:mfenced> <mml:mo>&gt;</mml:mo> <mml:mn>0.5</mml:mn> </mml:mrow> </mml:math> . The WGCNA showed a significant hub module comprising 267 DEGs. The major pathways of the hub genes involved in the PPI network at the highest confidence score $$&gt; 0.9$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mo>&gt;</mml:mo> <mml:mn>0.9</mml:mn> </mml:mrow> </mml:math> were related to mitochondrial translational elongation. The integrated gene transcriptional regulatory network revealed a TF (ETS1), two miRNAs (miR-34a-5 p and miR-205-5 p ) targeting a hub gene (GFM1) as the highest-order motif or subnetwork in the three-node miRNA feed-forward loop. Conclusions The study suggests that the regulatory feed-forward loop may provide a potential therapeutic target in CML. Consequently, the mitochondrial translation pathway may be explored as an alternative to BCR-ABL pathways, which could aid in eliminating or increasing sensitization of CML progenitor/stem cells to TKI treatment.