Researchers have found a genetic “sweet spot” in an aggressive form of acute myeloid leukaemia, offering hope of new treatments, it has been announced.
The study was led by an international team of researchers from the University of Birmingham, Newcastle University, the Princess Maxima Centre of Paediatric Oncology in the Netherlands, and University of Virginia in the USA. The team used advanced screening tools to identify how gene regulatory networks maintain FLT3-ITD mutated acute myeloid leukaemia (AML).
The results of their study are published in Cell Reports.
Using this AML model, they identified transcription factors (TFs) and the genes they control that, together, form a complex network that is highly specific for FLT3-ITD AML cells as compared to healthy cells.
Using a screening method developed by researchers in Newcastle, the researchers identified about 100 genes within this gene regulatory network important for AML growth and survival.
They focused on several of these genes to study the effect of targeting them, with particular focus on RUNX1, which showed that RUNX1 is a key factor in keeping the gene regulatory network stable.
Significantly, the RUNX1 protein could be blocked by using a small molecule inhibitor developed by Prof John Bushweller of the University of Virginia, which led to the collapse of the network that maintains FLT3-ITD AML.
Senior authors Professor Constanze Bonifer and Professor Peter Cockerill from the Institute of Cancer and Genomic Sciences at the University of Birmingham said: “The FLT3-ITD sub-type of acute myeloid leukaemia 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.
“We are delighted to have identified multiple factors, including TFs and signalling proteins that have key roles in maintaining these gene regulation networks where TFs and genes are wired in an AML- specific way.
“Such networks act a bit like a computer programme that runs processes to maintain AMLs and which are different to those networks found in normal cells. 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.”
Professor Olaf Heidenreich, of Newcastle University, and Dr Helen Blair, formerly of Newcastle and now at the Princess Maxima Centre for Paediatric Oncology in Utrecht said although genome-wide screening – which eliminates every gene in cancer cells to identify those that are essential for cancer growth – is often used, it also identifies many genes that are also required for healthy cells.
“Therefore, finding genes that are only important for cancer cells is a bit like finding a needle in a haystack,” they said. “Identifying the gene regulatory networks that are specific for cancer cells makes this much easier.”
Source:
Coleman DJL, Keane P, Luque-Martin R, Chin PS, Blair H, Ames L, Kellaway SG, Griffin J, Holmes E, Potluri S, Assi SA, Bushweller J, Heidenreich O, Cockerill PN, Bonifer C. (2023) “Finding and targeting a tumour’s sweet spot to eradicate aggressive form of leukaemia.” Cell Reports, doi: 10.1016/j.celrep.2023.113568
Link: https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01580-2
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