Credit: Lance Liotta
Understanding the relationship between mutated and wild-type genes could lead to new therapies for acute myeloid leukemia (AML), according to researchers.
The group discovered that RUNX1/ETO, generated by the chromosomal translocation t(8;21), regulates a leukemia-propagating transcriptional network via a dynamic equilibrium with RUNX1.
But depleting RUNX1/ETO prompts the formation of a transcriptional network that promotes myeloid differentiation.
Constanze Bonifer, PhD, of the University of Birmingham in the UK, and her colleagues detailed this work in Cell Reports.
The researchers likened normal hematopoiesis to a production line, with genes acting as regulators to control each step of blood formation. When a mutation occurs in the relevant regulator genes, the finely balanced order of the production line is disrupted, with drastic consequences.
Using digital footprinting and chromatin immunoprecipitation sequencing, the team showed that RUNX1/ETO switches off hundreds of other genes, many of them regulators themselves. As a consequence of the drastically altered production line, normal blood formation cannot happen, and leukemic cells form.
“Understanding how these rogue regulators operate is essential,” Dr Bonifer said. “[T]hese leukemic cells have one mutated gene and one unchanged one that would make the normal regulator. What happens in the leukemic cell is fundamentally a battle for supremacy between the two regulators, and the mutated one wins much of the time.”
“This is compounded by the normal regulator, which tries to compensate for defeat, and, in doing so, changes the output of genes that would be otherwise unaffected by the abnormal regulator. Quite simply, the result is a real mess. The cells are confused and can’t develop into mature blood cells.”
More specifically, the researchers found that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes.
Disrupting this equilibrium in t(8;21) cells by depleting RUNX1/ETO led to a global redistribution of transcription factor complexes within pre-existing open chromatin. And this prompted the formation of a transcriptional network that drives myeloid differentiation.
“If targeting [RUNX1/ETO] can reverse the changes it is making to the cellular production line, then it would ultimately point towards new avenues for a more precise treatment of leukemia,” said study author Olaf Heidenreich, PhD, of Newcastle University in the UK.
“Knowing that the production line can be restored to normal function gives us real hope. Of course, that is much easier to do in the lab than it is in the human body. But now we know how this works, we can look to deliver inhibitors to those mutated regulators. Creating one that works is the next step we have to overcome.”
