Epigenetic modifiers direct lineage switch in MLL-AF4 leukemia

Résumé fourni par la source

MLLr initiates onset of high-risk leukemia which lineage – ALL or AML – is determined by the MLL-fusion partner. MLL-AF4 pre-dominantly associates with B-ALL, however ~1% of cases convert from CD19+ lymphoid into CD19 neg myeloid phenotype. Here we aimed to identify molecular basis of lineage switching in a cohort of MLL-AF4 acute leukemia patients undergoing myeloid relapses. Performed genomic and transcriptomic studies revealed low mutational load and substantial changes in transcriptomic pattern observed at AML relapse. We found CHD4 gene, a core component of chromatin remodeling NuRD complex, to be disrupted in analyzed cases, pointing into its crucial function in maintenance of lymphoid commitment decisions. Comparison with non-lineage switching MLL-AF4 patients showed hyperactivation of translational processes and co-existence of two signatures at B-ALL stage of our patients: B-cell and multi-potent, progenitor-like. This data suggests that enhanced cellular plasticity may facilitate CD19 loss and myeloid differentiation, directed by dysfunctional epigenetic modifiers, leading to treatment escape route to e.g. epitope-directed immunotherapies. Publication History Article published online: 17 May 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

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