Pluto Bioinformatics

GSE119348: Dependence on Myb expression is attenuated in myeloid leukemia with N-terminal CEBPA mutations

Bulk RNA sequencing

Mutations altering the normal function of C/EBP are frequent in acute myeloid leukaemia with normal karyotype. MYB, a cooperating partner of C/EBP, is likewise heavily implicated in AML. Here we investigate how the relative requirement for the transcription factor MYB in AML relates to the particular combinations of wild type and mutated alleles of CEBPA. Through knockdown of Myb in murine cell lines modelling the spectrum of CEBPA mutations we show that the consequences of reduced Myb depend on the mutational status of Cebpa. Importantly, Myb knockdown fails to override the block in myeloid differentiation in cells with biallelic N-terminal C/EBP mutations, demonstrating for the first time that the dependency on Myb observed in AML is much lower in leukaemia with this combination of mutations. By comparing genome-wide analyses of gene expression following Myb knockdown and ChIP-seq data for the binding of C/EBP isoforms, we provide evidence for a functional cooperation between C/EBP and Myb in the maintenance of the leukaemia state. This co-dependency breaks down when both alleles of CEBPA harbour N-terminal mutations, as a subset of C/EBP-regulated genes only bind the short p30 C/EBP isoform and, unlike other C/EBP regulated genes, do so without a requirement for Myb. SOURCE: Pierre,Daniel,Cauchy ( - Laboratory Rudolf Grosschedl Max Planck Institute of Immunobiology and Epigenetics

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