15 February 2021

The first cellular model to depict the evolution of acute myeloid leukaemia (AML), from its early to late stages, has been built using the gene editing tool CRISPR/Cas9.

A research team led by the Icahn School of Medicine at Mount Sinai, New York, USA, used CRISPR to alter genes within induced pluripotent stem cells (iPSCs) – human cells which have the capacity to make any cell type in the body. They created a series of iPSCs with increasing numbers of mutations in three genes, ASXL1, SRSF2 and NRAS, and then induced the iPSCs to make blood cells.

In doing so, they recapitulated the progression from normal haematopoietic stem cells, to clonal haematopoiesis, myelodysplastic syndrome, and finally AML. They then showed that they could identify potential therapeutic targets for early disease stages.

Senior author Dr Eirini Papapetrou, associate professor of oncological sciences at Icahn Mount Sinai, said: “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.

“By creating the first cellular model to track the evolution of human leukaemia, we believe we’ve taken an important step toward unravelling the cellular biology of this disease. We've 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.

“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.”

Writing in the journal Cell Stem Cell, the researchers found inflammatory and innate immunity pathways which could be early targets for new treatments. They also 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.


Wang T, Pine AR, Kotini AG, Yuan H, Zamparo L, Starczynowski DT, Leslie C, Papapetrou EP. (2021) “Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets.” Cell Stem Cell, doi: 10.1016/j.stem.2021.01.011


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