Reversal of MYB-dependent suppression of MAFB expression overrides leukaemia phenotype in MLL-rearranged AML.

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.

Author Correction: High WBP5 expression correlates with elevation of HOX genes levels and is associated with inferior survival in patients with acute myeloid leukaemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

High WBP5 expression correlates with elevation of HOX genes levels and is associated with inferior survival in patients with acute myeloid leukaemia.

WW domain binding protein 5 (WBP5), also known as Transcriptional Elongation Factor A like 9 (TCEAL9) has been proposed as a candidate oncogene for human colorectal cancers with microsatellite instability and as a predictive indicator of small cell lung cancers. Furthermore, several independent studies have proposed WBP5, and its association with Wilms Tumor-1 (WT1) expression, as part of a gene expression-based risk score for predicting survival and clinical outcome in patients with Acute Myeloid Leukaemia (AML). To date, the prognostic significance of the sole WBP5 expression and its impact on the survival outcome in AML patients remains largely understudied. In the present study, we have made use of publicly available patient expression arrays and have developed an unbiased approach to classify AML patients into low versus high WBP5 expressers and to balance them for known mutations and cytogenetic findings. Interestingly, we found that patients characterized by high WBP5 expression displayed inferior overall and event-free survival rates. Notably, gene expression profiling showed that patients with high WBP5 had elevated expression of several HOX cluster genes, such as HOXA5, HOXA7, HOXA9 and HOXA10, and several of their partner proteins, such as MEIS1 and FOXC1, which have been demonstrated to be causative for AML. Taken together, our data suggest that WBP5 expression level could serve as an indicator for prognosis and survival outcome in patients with AML.

Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding.

The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.