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The collaboration has led to the first pre-clinical model of acute erythroid leukaemia.

Acute erythroid leukemia commonly involves both myeloid and erythroid lineage transformation. Di Genua et al. show that combined Cebpa and Gata2 mutations induce bi-lineage AEL. The Gata2 mutation (bottom soil layer) increases chromatin accessibility of erythroid transcription factor motifs (red roots) and decreases chromatin accessibility of myeloid transcription factor motifs (blue roots) while bi-allelic Cebpa mutation (top soil layer) increases erythroid transcription factor expression. This transforms neutrophil-monocyte progenitors into bi-potent leukemia-initiating cells that produce both myeloid and erythroid blasts (red and blue flowers, respectively). Artwork by Rae Cook.
Acute erythroid leukemia commonly involves both myeloid and erythroid lineage transformation. Di Genua et al. show that combined Cebpa and Gata2 mutations induce bi-lineage AEL. The Gata2 mutation (bottom soil layer) increases chromatin accessibility of erythroid transcription factor motifs (red roots) and decreases chromatin accessibility of myeloid transcription factor motifs (blue roots) while bi-allelic Cebpa mutation (top soil layer) increases erythroid transcription factor expression. This transforms neutrophil-monocyte progenitors into bi-potent leukemia-initiating cells that produce both myeloid and erythroid blasts (red and blue flowers, respectively). Artwork by Rae Cook.

Acute erythroid leukaemia (AEL) is a rare leukaemia (blood cancer) that has been difficult to study because there is no pre-clinical animal model for it. Now, in a study published in Cancer Cell, the Nerlov and Vyas groups have developed a pre-clinical mouse model for the disease, allowing researchers and clinicians to study the disease, identify potential drug targets and biomarkers, and find out how the disease starts.   

AEL can be more difficult to treat since there is more than one cell type that becomes malignant in the disease: erythroid or red blood cells (which carry oxygen around in the body), and myeloid cells (neutrophils and monocytes – they destroy and engulf bacteria). So far, researchers have not been able to find out which cancer-causing mutations cause AEL, and therefore there are no accurate experimental models to study the disease or develop new treatments: these models often rely on replicating known mutations to study the disease.

But researchers have found that cancerous cells in AEL patients often had mutations in two genes at the same time. These genes, known as CEBPA and GATA2, which both carry instructions for encode two proteins (C/EBPa and GATA-2) which are both transcription factors: they determine which genes are expressed in a particular cell. These mutations affect very specific parts of the two proteins, so to accurately model the disease, the MRC WIMM researchers genetically engineered mice so that their blood cells carried the exact same mutations found in human patients. Crucially, it was only when C/EBPa and GATA-2 mutations were combined that the mice developed the AEL hallmark of a leukaemia of both the erythroid and myeloid cell lineages.

Using the state-of-the-art genomics platforms at the MRC WIMM, including single-cell RNA-sequencing to analyse gene expression changes, ATAC-sequencing to analyse epigenetic changes, and cellular barcoding for lineage tracing, the researchers could demonstrate that the disease that developed in mice closely resembled human AEL.

Shared leukaemia-initiating cell 

The Nerlov and Vyas groups could identify a neutrophil-monocyte progenitor as the main cell type that was responsible for propagating the leukaemia. They found that the mutant C/EBPa and GATA-2 proteins transcriptionally and epigenetically ‘re-wired’ this progenitor cell so that it now produced neutrophils and erythrocytes, rather than neutrophils and monocytes, allowing both myeloid and erythroid cancerous cells to be made by the same leukaemia initiating cell.

Cristina Di Genua, who worked on the study, said: “Model systems play an important role in the understanding of leukaemia biology, identifying leukaemic initiating cells and can be used for drug screening, discovering novel druggable targets and biomarkers that could be used to specifically target leukaemic initiating cells. These findings generate a cellular and molecular framework for how acute erythroid leukaemia develops. There are currently no clear guidelines on how to treat AEL patients and this research provides a pre-clinical model that can now be used for the development of targeted treatments for this specific type of leukaemia.”

This study was funded by Bloodwise (now Blood Cancer UK) and the Medical Research Council.