Researchers at the Wellcome Sanger Institute, University of Cambridge, University of Nottingham, and their collaborators have found that a compound in eye drops that was being developed for the treatment of an eye disease also targets an essential cancer gene and could kill leukemia cells without harming non-leukemic blood cells.
The team’s study (“SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4”), published in Nature Communications, reveals a potential new therapeutic approach for acute myeloid leukemia (AML), an aggressive blood cancer with a poor prognosis.
“We recently identified the splicing kinase gene SRPK1 as a genetic vulnerability of acute myeloid leukemia. Here, we show that genetic or pharmacological inhibition of SRPK1 leads to cell cycle arrest, leukemic cell differentiation, and prolonged survival of mice transplanted with MLL-rearranged AML. RNA-seq analysis demonstrates that SRPK1 inhibition leads to altered isoform levels of many genes including several with established roles in leukemogenesis such as MYB, BRD4, and MED24,” wrote the investigators.
“We focus on BRD4 as its main isoforms have distinct molecular properties and find that SRPK1 inhibition produces a significant switch from the short to the long isoform at the mRNA and protein levels. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. We go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition. Our findings reveal that SRPK1 represents a plausible new therapeutic target against AML.”
Mainstream AML treatments have remained unchanged for over thirty years, with the current treatment being chemotherapy, and the majority of people’s cancer cannot be cured, according to the scientists. A subtype of AML, driven by rearrangements in the MLL gene, has a particularly bad prognosis.
In a previous study, researchers at the Sanger Institute developed an approach, based on CRISPR gene editing technology, which helped them identify more than 400 genes as possible therapeutic targets for different subtypes of AML. One of the genes, SRPK1, was found to be essential for the growth of MLL-rearranged AML. SRPK1 is involved in RNA splicing.
In a new study, Sanger Institute researchers and their collaborators set out to determine how inhibition of SRPK1 can kill AML cells and whether it has therapeutic potential in this disease. They first showed that genetic disruption of SRPK1 stopped the growth of MLL-rearranged AML cells and then went on to study the compound SPHINX31, an inhibitor of SRPK1, which was being used to develop an eye-drop treatment for retinal neovascular disease.
The team found that the compound strongly inhibited the growth of several MLL-rearranged AML cell lines, but did not inhibit the growth of normal blood stem cells. They then transplanted patient-derived human AML cells into immunocompromised mice and treated them with the compound. The growth of AML cells was strongly inhibited and the mice did not show any noticeable side effects.
George Vassiliou, Ph.D., joint leader of the research from the Wellcome Sanger Institute and the Wellcome-MRC Cambridge Stem Cell Institute, noted that, “We have discovered that inhibiting a key gene with a compound being developed for an eye condition can stop the growth of an aggressive form of acute myeloid leukemia without harming healthy cells. This shows promise as a potential approach for treating this aggressive leukemia in humans.”
Konstantinos Tzelepis, Ph.D., joint lead author from the Wellcome Sanger Institute and the University of Cambridge, added, “Our study describes a novel mechanism required for leukemia cell survival and highlights the therapeutic potential of SRPK1 inhibition in an aggressive type of AML. Targeting this mechanism may be effective in other cancers where BRD4 and SRPK1 play a role, such as metastatic breast cancer.”
