Scientists have discovered clues of how a specific variant of the RUNX1 gene raises risk of leukaemia in people with Down’s syndrome.
Abnormal numbers of chromosomes, in particular chromosome 21, is a common genetic alteration in leukaemia. People who are born with an extra copy of chromosome 21, known as ‘trisomy 21’ or Down’s syndrome, are at high risk of developing acute myeloid leukaemia (AML). However, to date, mechanistic studies have been unable to explain why this is the case, and which genes on chromosome 21 are responsible for leukaemia predisposition.
So a team led by Professor Jan-Henning Klusmann, of the University Hospital Frankfurt, and Professor Dirk Heckl, of Martin-Luther-University Halle-Wittenberg, Germany, set out to investigate. They used CRISPR gene screening in cells from people with Down’s syndrome and myeloid leukaemia. They found these Down’s syndrome-associated AML cells have a “strong and specific dependency” on the RUNX1 gene.
Further investigation revealed that the production of one particular variant of RUNX1 – called RUNX1a – is elevated in these patients.
Tests on mouse models showed that excess RUNX1a acts together with the Gata1s version of the Gata1 gene, to increase risk of leukaemia.
It does so by displacing RUNX1c from its binding sites, triggering cancer-causing pathways involving proteins MAX and MYC. Further tests showed that this effect was reversed by restoring the balance between RUNX1a and RUNX1c, or by blocking the interaction between MAX and MYC.
Publishing their findings in the journal Blood, the authors write: “Our study paves the way for the development of specific and targeted therapies for Down syndrome associated acute myeloid leukaemia, as well as for other leukaemias.”
Professor Klusmann said: “Thanks to our research results, we now have a better understanding of what happens in leukemogenesis.
“The study underlines how important it is to examine all gene variants in carcinogenesis. In many cases, certain mutations in cancer cells alter how these variants form.”
Gialesaki S, Bräuer-Hartmann D, Issa H, Bhayadia R, Alejo-Valle O, Verboon L, Schmell AL, Laszig S, Regényi E, Schuschel K, Labuhn M, Ng M, Winkler R, Ihling C, Sinz A, Glaß M, Hüttelmaier S, Matzk S, Schmid L, Strüwe FJ, Kadel SK, Reinhardt D, Yaspo ML, Heckl D, Klusmann JH. (2023) “RUNX1 isoform disequilibrium promotes the development of trisomy 21 associated myeloid leukemia.” Blood, doi: 10.1182/blood.2022017619
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