How gene regulatory networks maintain FLT3-ITD mutated AML

The use of shRNA screening has enabled researchers to investigate the roles of individual specific factors in maintaining the network seen in AML.


An international team of scientists from the University of Birmingham, Newcastle University, University of Virginia, and the Princess Maxima Center of Pediatric Oncology in Utrecht used advanced screening tools to determine how gene regulatory networks (GRNs ) persistence of a sub-type of blood cancer. called FLT3-ITD mutated AML.

Acute Myeloid Leukemia, a very aggressive common form of leukemia is activated by mutations in signaling molecules that are 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 (TF) and the genes they bind to in a complex network (GRN) that is more specific for FLT3 cells -ITD AML compared to healthy cells.

The team found 100 genes within the GRN, using a screening method developed in Newcastle, that are important for the growth and survival of AML. They studied some of these genes in more detail to observe the effect of targeting them. TF RUNX1 analysis showed that RUNX1 is an important factor in maintaining GRN stable.

In particular, the RUNX1 protein can be blocked by using a small molecule inhibitor developed by Dr. John Bushweller at the University of Virginia. This molecule leads to the collapse of the network that maintains FLT3-ITD AML.

The paper’s senior authors Dr Constanze Bonifer and Dr Peter Cockerill, from the Institute of Cancer and Genomic Sciences at the University of Birmingham said: The FLT3-ITD sub-type of acute myeloid leukemia we studied had poor prognosis. results in high relapse rates among people who go into remission. We set out to identify the more specific targets needed for AML cancer cells to control themselves, which could lead to new treatments.

They continued: “Such networks act like a computer program that runs the processes to maintain AMLs and are different from the networks found in normal cells. Our research found that knocking out those causes the network to shut down, and that can lead to the death of cancer cells because they can no longer replicate.

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

A type of screening technique called shRNA enabled the team to investigate individual specific factors that play a role in maintaining the network found in AML. As TFs function within an interactive network, the team then observes the effect of targeting individual factors on the rest of the network. They found that specific proteins including RUNX1 are key for maintaining the entire GRN.

Dr Olaf Heidenreich, now at the Princess Maxima Center for Pediatric Oncology in Utrecht, commented: Many researchers in the world are using techniques called genome wide screening where they eliminate every gene in cancer cells to identify those genes which is necessary for the growth of these cells. However, this method identifies many genes that are also required for healthy cells. Therefore, finding genes that are important only for cancer cells is like finding a needle in a haystack.

He concluded: In addition to testing the impact of selected targets on the growth of AML, our work will provide an important resource for the scientific community to pursue targets that are important.

This study was published in Cell Reports.

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