Gene Expression Network and Circ_0008012 Promote Progression in MLL/AF4 Positive Acute Lymphoblastic Leukemia

Abstract

Background: Acute lymphoblastic leukemia with MLL/AF4 rearrangement remains a major hurdle to improving outcomes. Gene network and circRNAs have been found to participate in tumorigenesis, while their roles in leukemia still need to be explored. Recent patents have shown that circRNAs exhibit the markers for the children ALL, although the target and related mechanism remain to be elucidated.

Objective: This study aims to explore the possible targets and mechanisms of ALL with MLLAF4 rearrangement.

Methods: We first generated a gene network focusing on MLL-AF4 rearrangement. Cell viability was determined with Cell Counting Kit-8 assay. The cell apoptosis was tested by the Annexin V/PI assay. The RNA-protein complexes were analyzed by qRT-PCR, and the pathway proteins were analyzed by western blot.

Results: This gene network was associated with biological processes, such as nucleic acid metabolism and immunity, indicating its key role in inflammation. We found that circ_0008012 was upregulated in MLL/AF4 ALL cells and regulated cell proliferation and apoptosis. Further computed simulation and RIP showed that IKKβ was the strongest protein in the NF-κB pathway binding with circ_0008012. As a result, possible regulation of circ_0008012 is suggested by binding IKKβ in the IKKα:IKKβ:IKKγ compound, which then phosphorylates IκB and activates NF- κB:p65:p300 compound in cell nucleus, thereby leading to leukemia.

Conclusion: We identified a gene network for MLL/AF4 ALL. Moreover, circ_0008012 may be a therapeutic target for this subtype of ALL.

Keywords: ALL; IKKβ; MLL/AF4 rearrangement; NF-κB; circ_0008012; gene network.