Polycomb Alterations in Acute Myeloid Leukaemia: From Structure to Function

SIMPLE SUMMARY: Epigenetic factors control how genes are expressed in different cell types. Members of the Polycomb Repressive Complexes (PRCs) are critical for epigenetic control of gene transcription in blood cells, and mutations and deletions in these factors are common in the blood cancer acute myeloid leukaemia (AML). This review article provides an overview of how the structure and function of PRCs are affected by genetic alterations in AML, with a primary focus on PRC2 core factors. We document how mutations and deletions in PRC2 factors are linked to other AML-associated genetic alterations and discuss how these observations might inform potential treatment avenues in future. ABSTRACT: Epigenetic dysregulation is a hallmark of many haematological malignancies and is very frequent in acute myeloid leukaemia (AML). A cardinal example is the altered activity of the Polycomb Repressive Complex 2 (PRC2) due to somatic mutations and deletions in genes encoding PRC2 core factors that are necessary for correct complex assembly. These genetic alterations typically lead to reduced histone methyltransferase activity that, in turn, has been strongly linked to poor prognosis and chemoresistance. In this review, we provide an overview of genetic alterations of PRC components in AML, with particular reference to structural and functional features of PRC2 factors. We further review genetic interactions between these alterations and other AML-associated mutations in both adult and paediatric leukaemias. Finally, we discuss reported prognostic links between PRC2 mutations and deletions and disease outcomes and potential implications for therapy.