Identifying MHC-II regulators that enable immune escape in acute myeloid leukaemia

Relapse of acute myeloid leukaemia (AML) following allogeneic stem cell transplantation (alloSCT) confers a dismal prognosis, due to a paucity of effective salvage options.  Recent studies have linked post-alloSCT relapse of AML to non-genomic MHC-II silencing on leukaemic blasts, although the exact mechanism of MHC-II repression remains unknown.

Utilising unbiased CRISPR/Cas9 screens, we identify that the CtBP co-repressor complex transcriptionally represses MHC-II pathway genes, while the ubiquitin ligase FBXO11 mediates degradation of CIITA, the principal transcription factor controlling MHC-II expression.  Targeting these specific repressive mechanisms induces MHC-II expression across a range of AML cell lines and stimulates potent CD4⁺ T cell-based anti-tumour immune responses.  These findings provide fundamental insights into the graft-versus leukaemia effect and establish the rationale for therapeutic strategies aimed at restoring tumour cell MHC-II expression to salvage AML relapse after alloSCT.

Kah Lok Chan is a consultant haematologist and PhD student in the Cancer Epigenetics laboratory at the Peter MacCallum Cancer Centre.  He obtained his undergraduate medical degree from the University of Melbourne in 2009 and subsequently completed joint specialist training in haematology in 2018 through the Royal Australasian College of Physicians and the Royal College of Pathologists of Australasia.  He is currently completing his PhD under the supervision of Professor Mark Dawson and Associate Professor Marian Burr, focused on identifying epigenetic mechanisms of cancer immune evasion that can be targeted to improve immunotherapy outcomes.