Ablation of MYB-dependent leukaemia phenotype in MLL-driven AML correlates with increased expression of MAFB.

Abstract

The transcription factor MYB plays a pivotal role in haematopoietic homeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). Our previous work has demonstrated that not all AML types display the same dependency on MYB expression and that MYB dependence is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML still remains to be further elucidated. In this study, we investigate the importance of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-fusion-driven leukaemia upon MYB suppression is not seen in AML cells with a complex karyotype. By performing transcriptome analysis, we demonstrate that a strong activation of MAFB expression driven by MYB ablation is restricted to MYB-dependent cells. In line with these observations, stratification of publicly available patient data reveals a reciprocal relationship between the expression of MYB and MAFB, highlighting a novel connection between those two factors in AML.