PDF(Pubmed)
Abstract：
The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role 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-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.
摘要：
转录因子MYB在造血同质平衡中起关键作用，其异常表达与急性髓性白血病（AML）的发生和维持有关。我们先前已经证明,并非所有AML亚型都显示对MYB表达的相同依赖性,并且这种变异性由驱动突变的性质决定。然而,MYB依赖性的这种差异是否是AML的总体趋势还有待进一步阐明.这里,我们通过在具有不同驱动病变的AML细胞系模型中进行siRNA介导的敲减,研究了MYB在人白血病中的作用.我们表明，在MLL重排和t（8;21）白血病中观察到的MLL重排和MYB抑制后的骨髓样分化的特征性减少和伴随的诱导在具有复杂核型的AML细胞中没有看到。转录组分析显示，MYB消融在MYB依赖性细胞中产生MAFB表达的一致增加，有趣的是,MAFB的异位表达可以表型复制MYB抑制的作用。因此，AML患者分子数据的计算机分层分析显示MYB和MAFB表达之间存在相互关系，强调AML中这两个因素之间的新的生物学相互联系,并支持MLL重排白血病中MAFB靶向的新原理。
