CRISPR used to model acute myeloid leukaemia progression

A research team has built the first cellular model to depict the evolution of acute myeloid leukaemia (AML) from its early to late stages. By using CRISPR gene editing technologies to alter genes that make cells malignant, the team was able to identify potential therapeutic targets for early disease stages. The study was led by the Icahn School of Medicine at Mount Sinai (Icahn Mount Sinai), US. 

According to the researchers, the therapeutic targets could be applicable not just to AML but also to the blood cancer myelodysplastic syndrome and clonal haematopoiesis, which is often a pre-leukaemic condition.

“We essentially built from scratch a model of leukaemia that characterises the molecular changes that underlie progression of the disease and which allowed us to identify the earliest events in its development that can be therapeutically targeted,” said Associate Professor Eirini Papapetrou, senior author of the study. “By creating the first cellular model to track the evolution of human leukaemia, we believe we have taken an important step toward unravelling the cellular biology of this disease. We have identified molecular vulnerabilities that occur early in the disease process which could potentially lead to improved biomarkers and novel treatments for AML – goals that have proven so elusive to medical science in the past.”

By introducing specific leukaemia-causing gene mutations through CRISPR-mediated gene editing, the researchers were determined to better understand the successive stages of the evolution of the condition. CRISPR allowed the team to alter the DNA sequences in induced pluripotent stem cells (iPSCs) to create a model with an increasing number of mutated genes that shows progressive malignant features that correspond to their human counterparts in myeloid disease. 

“CRISPR-Cas9 and iPSC technologies gave us the unique opportunity to characterise changes underlying the transitions between stages of AML and to harness patterns of these changes to pinpoint target genes for early intervention,” explained Papapetrou.

The team found that inflammatory and innate immunity pathways constitute such early targets and demonstrated that inhibitors of these pathways, therapies that are being trialled in blood cancers and immune-related disorders, may be promising therapeutic modalities for AML and myelodysplastic syndrome.

The study was published in Cell Stem Cell.