A treatment under development for eye disease may also be effective against acute myeloid leukaemia (AML), British researchers have reported.
The discovery follows a detailed genetic analysis previously carried out at the Wellcome Sanger Institute, in Cambridge. The scientists discovered that a gene SRPK1 is essential for the development of a subtype of AML driven by rearrangements in the MLL gene.
SRPK1 is involved in RNA splicing – and the current study found that inhibiting it can kill AML cells. This led the scientists, in turn, to a compound called SPHINX31, which inhibits SRPK1. The compound is already being testing at the University of Nottingham as an eye drop treatment for retinal neovascular disease.
Pre-clinical studies in cell lines and mice both showed that SPHINX31 can stop the growth of MLL-rearranged AML cells but has no effect on normal blood stem cells. What’s more, mice treated with SPHINX31 showed no indication of side-effects, the researchers report in the journal Nature Communications.
They went on to show that the anti-AML effect was mediated in part by changes to the splicing of the RNA for BRD4, a gene which has already been associated with AML. Inhibiting SRPK1 causes the main form of BRD4 to switch to another form, a change which reduces AML growth.
Dr Konstantinos Tzelepis from the Wellcome Sanger Institute, joint leader of the research, said: “Our study describes a novel mechanism required for leukaemia cell survival and highlights the therapeutic potential of SRPK1 inhibition in an aggressive type of AML.”
He added: “Targeting this mechanism may be effective in other cancers where BRD4 and SRPK1 play a role, such as metastatic breast cancer.”
Source: Tzelepis, K., De Braekeleer, E., Aspris, D., Barbieri, I., Vijayabaskar, M. S., Liu, W.-H., Gozdecka, M., Metzakopian, E., Toop, H.D., Dudek, M., Robson, S.C., Hermida-Prado, F., Yang, Y.H., Babaei-Jadidi, R., Garyfallos, D.A., Ponstingl, H., Dias, J.M.L., Gallipoli, P., Seiler, M., Buonamici, S., Vick, B., Bannister, A.J., Rad, R., Prinjha, R.K., Marioni, J.C., Huntly, R., Batson, J., Morris, J.C., Pina, C., Bradley, A., Jeremias, I., Bates, D.O., Yusa, K., Kouzarides, T., Vassiliou, G.S. (2018) “SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4”, Nature Communications, available from doi: 10.1038/s41467-018-07620-0
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