Removal of RUNX1 TF, Gene Targeting May Contribute to Eradication of AML Cancer Cells

A network of interacting genes activated by mutations in signaling molecules associated with the highly aggressive form of leukemia acute myeloid leukemia (AML) may be manipulated to induce cell death in AML cancer cells, according to the authors of a study published in Cell Reports. Using screening tools, the study authors identified connections between transcription factor (TF) proteins and the gene regulatory network (GRN) that is specific to FLT3-ITD mutated AML.

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In addition, the researchers determined that approximately 100 genes within the GRN were important for the survival and growth of AML. In particular, the TF RUNX1 presented to be a key factor in the GRN’s stability. Blocking this protein with a small molecule inhibitor would lead to the collapse of the network that sustains FLT3-ITD AML.

“The FLT3-ITD sub-type of [AML] that we have been studying has very poor outcomes with high relapse rates among those who do go into remission. We set out to identify very specific targets that are required for AML cancer cells to regulate themselves, that could potentially lead to new treatments,” said senior study author Constanze Bonifer, PhD, Institute of Cancer and Genomic Sciences at the University of Birmingham, in a press release.

In order to identify additional protein targets that regulate AML cancer cells, the researchers mapped TF binding sites within AML-expressed genes. Through this process, the investigators determined which cells were normal or malignant, and the malignant cells were specifically targeted.

“We are delighted to have identified multiple factors, including TFs and signaling proteins that have key roles in maintaining these GRNs where TFs and genes are wired in an AML-specific way. Such networks act a bit like a computer program that runs processes to maintain AMLs, which are different to those networks found in normal cells,” said senior study author professor Peter Cockerill, BSc, PhD, Institute of Cancer and Genomic Sciences at the University of Birmingham, in the press release. “Our research has found that knocking out such factors resulted in the network shutting down, and which may lead to the cancer cells dying off as they are unable to replicate.”

The investigators specifically highlight the use of shRNA, a screening technique to look at individual TFs’ roles within the network. Because TFs function in an interactive network, the investigators found the effect of targeting individual TFs on the rest of the network and particular proteins—including RUNX1—were necessary for the overall maintenance of the GRN.

“Many researchers in the world use techniques called ‘genome wide screening’ where they eliminate every gene in cancer cells to identify those genes that are essential for the growth of these cells; however, this method identifies many genes that are also required for healthy cells…Identifying the GRNs that are specific for cancer cells makes [these] talks much easier,” said co-grant holder Olaf Heidenreich, PhD, Princess Maxima Centre for Pediatric Oncology, in the press release. “Besides testing the effect of select targets on AML growth, our work will provide an important resource for the scientific community to home in on the targets that really matter.”

Reference

University of Birmingham. Finding and targeting a tumour’s sweet spot to eradicate aggressive form of leukemia. News release. December 20, 2023. Accessed January 4, 2024. https://www.eurekalert.org/news-releases/1029619