Genome-wide Analysis of Transcriptional Reprogramming in Mouse Models of Acute Myeloid Leukaemia. Mus musculus

Acute leukaemias are commonly caused by mutations that corrupt the transcriptional circuitry of haematopoietic stem/progenitor cells. However, the mechanisms underlying large-scale transcriptional reprogramming remain largely unknown. Here we investigated transcriptional reprogramming at genome-scale in mouse retroviral transplant models of acute myeloid leukaemia (AML) using both gene-expression profiling and ChIP-sequencing. We identified several thousand candidate regulatory regions with altered levels of histone acetylation which were characterised by differential distribution of consensus motifs for key haematopoietic transcription factors. The integrated genome-scale analysis applied in this study represents a valuable and widely applicable approach to study the transcriptional control of both normal and aberrant haematopoiesis and to identify critical factors responsible for transcriptional reprogramming in human cancer. Overall design: To monitor global expression changes during leukaemia progression for both MLL-ENL and MOZ-TIF1, we performed gene expression profiling for three biological replicates each of the lin-/kit+ bone marrow (WT), Factor-Dependent Cells Patterson-Mix cells (FDCP), MLL-ENL initiation (ME-I), MOZ-TIF2 initiation (MT-I), MLL-ENL progression (ME-L) and MOZ-TIF2 progression (MT-L) samples. Biotin-labelled cRNA from three biological replicates was generated from 250ng of total RNA and hybridized onto MouseWG-6 version 2 Expression Bead Chips.