Epigenetic regulator genes direct lineage switching in MLL-AF4 leukaemia

Abstract

The fusion gene MLL-AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. However, relapse can be associated with a switch from acute lymphoblastic to acute myeloid leukaemia. Here we show that these myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate in either early, multipotent progenitors or committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes indicating that the execution and maintenance of lymphoid lineage differentiation is impaired. We show that this subversion is recurrently associated with the dysregulation of repressive chromatin modifiers, notably the nucleosome remodelling and deacetylation complex, NuRD. In addition to mutations, we show differential expression or alternative splicing of NuRD members and other genes is able to reprogram the B lymphoid into a myeloid gene regulatory network. Lineage switching in MLL-AF4 leukaemia is therefore driven and maintained by defunct epigenetic regulation.

Immunosuppression in tumor immune microenvironment and its optimization from CAR-T cell therapy

“…This mechanism is probably connected to gene mutations at the antigen locus due to immune pressure by CAR-T cells 114 . Lineage switch is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs in tumor cells, including alternative splicing 115 . Antigen-low escape indicated that CAR-T cells targeting specific antigens were unable to effectively eliminate specific antigens-low cells 116 .…”