CRISPR Gene Editing Used to Build 1st Model of AML Progression

CRISPR Gene Editing Used to Build 1st Model of AML Progression

Blocking early inflammatory and innate immune signaling is a promising therapeutic target in acute myeloid leukemia (AML), as disruptions in these signaling pathways occur early and persist throughout the evolution of the disorder.

This result comes from a recent study, in which researchers used CRISPR-Cas9 gene editing to observe how single healthy cells could become AML cancer cells, mapping the successive changes along the way.

The study, “Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets,” was published in the journal Cell Stem Cell.

“We essentially built from scratch a model of leukemia that characterizes 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,” Eirini Papapetrou, MD, PhD, the study’s lead author, said in a press release.

Papapetrou and her colleagues developed their model using induced pluripotent stem cells (iPSCs), which are adult cells that scientists can reprogram to adopt an early, stem cell-like state, from which many other types of cells can be grown.

They used CRISPR-Cas9 gene editing technology — a way to make targeted changes in a cell’s DNA — to sequentially introduce three mutations into their iPSCs that progressively drove AML formation.

The different stages of growth of these iPSCs, from stem cell to mature blood cell, also capture distinct pre-cancerous stages that end in leukemia, and that recreate genetic signatures of myelodysplastic syndrome (MDS; another type of blood cancer that can progress to AML) and AML.

At each step of the way, the team mapped out the changes taking place in gene activity that spurred the transitions between stages.

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

The investigators found that inflammatory and innate immune signaling became dysregulated early in the development of cells that led to AML. This early imbalance persisted in these cells, indicating that it is critical to the evolution of AML and, therefore, that inhibiting the various steps in the process make potential therapeutic targets.

Of interest, these targets might also apply to MDS and clonal hematopoiesis — when hematopoietic stem cells start making cells with the same genetic mutation — which frequently leads to leukemias.

“By creating the first cellular model to track the evolution of human leukemia,” Papapetrou said, “we believe we’ve taken an important step toward unraveling 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.”