Individuals with a 3rd copy of chromosome 21, often called trisomy 21, are at high risk of developing Acute Myeloid Leukaemia (AML), an aggressive type of blood cancer. Scientists led by the Department of Paediatrics at University Hospital Frankfurt have now identified the cause: although the extra chromosome 21 results in increased gene dosage of many genes, it’s above all of the perturbation of the RUNX1 gene – a gene that regulates many other genes – that appears to be accountable for AML pathogenesis. Targeting the perturbed regulator could pave the way in which for brand spanking new therapies.

Leukemia (blood cancer) is a gaggle of malignant and aggressive diseases of the blood-forming cells within the bone marrow. Very intensive chemotherapy and in some cases a bone marrow transplant are the one cure. Like all cancers, leukemia is brought on by changes within the DNA, the heredity material present in human cells in the shape of 46 chromosomes. In lots of types of leukemia, large parts of those chromosomes are altered. Individuals with Down syndrome, who’ve three copies of chromosome 21 (trisomy 21) are highly vulnerable: the danger of developing aggressive Acute Myeloid Leukaemia (AML) in the primary 4 years of their life is greater than 100 times greater for kids with Down syndrome. Down syndrome is essentially the most common congenital genetic disorder, affecting about one in 700 newborn babies.

RUNX1 transcription factor is responsible

The research group led by Professor Jan-Henning Klusmann, Director of the Department of Paediatric and Adolescent Medicine at University Hospital Frankfurt, has now discovered how the extra chromosome 21 can promote AML. With the assistance of genetic scissors (CRISPR-Cas9), they examined each of the 218 genes on chromosome 21 for its carcinogenic effect. It emerged that the RUNX1 gene is accountable for the chromosome’s specific carcinogenic properties. In further analyses, the researchers were capable of corroborate that just one particular variant – or isoform – of the gene promotes the event of leukemia.

Other RUNX1 isoforms were even capable of prevent the cells from degenerating. This explains why RUNX1 has to date not stood out – in several many years of in depth cancer research.”

Professor Jan-Henning Klusmann, Director of the Department of Paediatric and Adolescent Medicine at University Hospital Frankfurt

The RUNX1 gene encodes a “transcription factor” – a protein accountable for regulating the activity of other genes. RUNX1 regulates many processes, including embryonic development and early and late hematopoiesis, or blood formation. Disruption of this essential regulator is subsequently a key event in the event of AML. “Due to our research results, we now have a greater understanding of what happens in leukemogenesis,” explains Klusmann, an authority in pediatric cancer. “The study underlines how essential it’s to look at all gene variants in carcinogenesis. In lots of cases, certain mutations in cancer cells alter how these variants form,” he says.

Development of more sophisticated therapeutic approaches

These insights are essential for a greater understanding of the complex mechanisms of carcinogenesis, as Klusmann explains: “In this fashion, we’ve got laid the groundwork for developing more sophisticated therapeutic approaches. Through our biochemical analyses, we now know exactly how the gene variant alters the blood cells. From there, we were capable of use specific substances that block the disease mechanism.” The intention now’s to further explore the effect of those substances to be used in medical care. Klusmann: “On the idea of our expertise, we now wish to develop therapies to correct this malfunction. Applying them in clinical practice will definitely take just a few more years, but hopefully they are going to lead in the long run to sparing our young patients from intensive chemotherapy.”

Source:

Goethe University Frankfurt

Journal reference:

Gialesaki, S., et al. (2023) RUNX1 isoform disequilibrium promotes the event of trisomy 21 associated myeloid leukemia. Blood. doi.org/10.1182/blood.2022017619.