Researchers have discovered a new molecular pathway which could be used to treat acute myeloid leukaemia (AML)
The team from University of Pennsylvania, USA, used CRISPR gene editing technology screening to identify a therapeutic target known as ZMYND8. It is not a gene mutated in AML, but a protein which ‘reads’ epigenetic changes – chemical changes to the DNA and protein complex known as chromatin. It controls gene activity in AML and allow the continued growth of the cancer, according to the researchers.
Dr Junwei Shi from the University of Pennsylvania and colleagues say that a therapy targeting this new pathway could reduce side effects compared with current chemotherapy approaches. Details were published in the journal Molecular Cell recently.
CRISPR allows simultaneous screening of thousands of specific protein areas for their effect on cells. It can map and then disrupt the function of different proteins – and regions within these proteins – in cancer cells.
Dr Shi says: “We’ve discovered that cancer cells in patients with acute myeloid leukaemia rely heavily on ZMYND8, and thanks to a sophisticated CRISPR-based screening approach, we pinpointed the exact ‘druggable pocket’ to target.”
In experiments with mice, when the epigenetic ‘reader’ function of ZMYND8 was disrupted, mice grew smaller tumours and showed better survival, Dr Shi said.
Co-author Zhendong Cao added: “The findings suggest that delivering drug inhibitors against ZMYND8 could disrupt the acute myeloid leukaemia vulnerable gene regulation circuits.“
“It’s an opportunity to develop better precision medicine compounds than current treatments to treat this blood cancer which we are currently working on right now.”
Co-author Dr Shelley Berger commented: “Many genetic and epigenetic alterations have been identified in cancer but few are actionable targets. CRISPR revealed here, for the time, an unexpected epigenetic-linked molecular circuity that acute myeloid leukaemia is dependent on, and one that we can potentially manipulate.”
Cao Z, Budinich KA, Huang H, Ren D, Lu B, Zhang Z, Chen Q, Zhou Y, Huang YH, Alikarami F, Kingsley MC, Lenard AK, Wakabayashi A, Khandros E, Bailis W, Qi J, Carroll MP, Blobel GA, Faryabi RB, Bernt KM, Berger SL, Shi J. (2021) “ZMYND8-regulated IRF8 transcription axis is an acute myeloid leukemia dependency.” Molecular Cell, doi: 10.1016/j.molcel.2021.07.018
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