How gene regulatory networks maintain FLT3-ITD mutated AML

An international team of scientists from the Universities of Birmingham, Newcastle University, the University of Virginia and the Princess Máxima Pediatric Oncology Center in Utrecht used advanced screening tools to determine how a gene regulatory network (GRN) maintains a blood cancer subtype called FLT3 -ITD mutant AML.

Acute myeloid leukemia is a very aggressive common form of leukemia activated by mutations in signaling molecules and maintained by a network of regulatory proteins downstream of these signals. New research shows that this network can be manipulated to kill AML cells.

Using an AML model, the researchers identified connections between transcription factors (TFs) and the genes they bind, which together form a complex network (GRN) that exerts effects on FLT3-ITD AML cells compared with healthy cells. Highly specific.

Using a screening method developed in Newcastle, the team discovered 100 genes in GRN that are important for the growth and survival of AML. They studied several of these genes in more detail to see the effects of targeting them. Analysis of TF RUNX1 revealed that RUNX1 is a key factor in maintaining GRN stability.

Notably, the RUNX1 protein can be blocked by using small molecule inhibitors developed by Dr. John Bushweller of the University of Virginia. This molecule causes the collapse of the network that sustains FLT3-ITD AML.

“The FLT3-ITD subtype of acute myeloid leukemia we have been studying has a very poor prognosis and a high mortality rate,” said the paper’s senior authors Dr Constanze Bonifer and Dr Peter Cockerill from the Institute of Cancer and Genome Sciences at the University of Birmingham. Relapse rates among patients who enter remission. We set out to identify very specific targets required for AML cancer cell self-regulation, which may lead to new treatments.

They continued: “This network behaves somewhat like a computer program running the processes that maintain AML, and is different from the network found in normal cells. Our study found that removing these factors causes the network to shut down, which may This causes cancer cells to die due to their inability to replicate.

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Researchers mapped transcription factor binding sites within AML-specific expressed genes to identify potential protein targets that regulate AML cancer cells. They then compared normal cells with malignant cells to discover which genes promote AML survival and specifically target them.

A screening technique called shRNA allowed the team to study the role of individual specific factors in maintaining the networks found in AML. As TF operated in an interactive network, the team then observed the impact of targeting a single factor on the rest of the network. They found that specific proteins, including RUNX1, are key to maintaining the entire GRN.

Dr. Olaf Heidenreich, now at the Princess Máxima Center for Pediatric Oncology in Utrecht, commented: Many researchers around the world are using a technique called genome-wide screening, which eliminates every gene in cancer cells, to identify threats to these cells. Genes critical for growth. . However, this method identified many genes that are also required by healthy cells. So finding genes that are only important in cancer cells is a bit like looking for a needle in a haystack.

He concluded: In addition to testing the impact of selected targets on AML growth, our work will provide the scientific community with an important resource to study targets that really matter.

This research was published in cell report.