Curbing clonal hematopoiesis to prevent leukemia

A genetic mutation can transform a healthy, diverse blood stem cell population into one in which a single mutant clone predominates. (Images: Zebrafish red blood cells in the peripheral blood of normal and mutated zebrafish, Jonathan Henninger, PhD, and Serine Avagyan, MD, PhD, Zon lab, Boston Children’s Hospital)

As we age, many of us acquire mutations that cause some of our blood stem cells to multiply faster than others, forming their own distinct populations or “clones.” This is known as clonal hematopoiesis. In some cases, a single clone derived from a single genetically altered or mutated stem cell can expand to 30 percent of a person’s blood cells.

If such a “rogue” clone gets more mutations, it can lead to myelodysplasia, a rare blood disease, and in turn to leukemia. The lab of Leonard Zon, MD, director of the Stem Cell Research program at Boston Children’s Hospital, wondered if these rogue populations could be nipped in the bud, preventing a potentially fatal leukemia from developing.

If you could understand how blood stem cell clones become cancer, you could target the offending clone causing the problem.”

If so, it could help both adults who develop clonal hematopoiesis as they age, and children with a variety of blood disorders such as Shwachman-Diamond syndrome, GATA2 deficiency, or RUNX1 familial platelet disease, where clonal hematopoiesis can develop in childhood. develop.

“These children have a germline mutation that puts them at risk of developing leukemia earlier in life,” explains Serine Avagyan, MD, PhD, a pediatric oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and a fellow in the Sun lab. from . “They can develop clonal hematopoiesis in adolescence and sometimes at a younger age. We think these predisposition syndromes accelerate the process of clonal hematopoiesis, resulting in early leukemia.”

Tracking blood stem cells with colored ‘barcodes’

Certain stem cell populations are likely to dominate — and eventually become cancerous — because they gain some sort of edge through a genetic mutation. Or, as Charles Darwin would have put it, they get more ‘fit’. But how?

“If you could understand how blood stem cell clones become cancerous, you could target the clone causing the problem specifically,” Zon says.

That’s where Zon’s team, led by Avagyan and Jonathan Henninger, PhD, now at the Whitehead Institute for Biomedical Research, turned to zebrafish. A favorite resource of the Zon Lab, zebrafish are easy to breed and their embryos are translucent. That translucent quality allows scientists to view the development of blood cells in real time and observe the effects of various genetic mutations.

The zebrafish facility at Boston Children’s (Photo: KC Cohen)

Once a faulty gene is found, scientists can test multiple drugs on a large scale simply by adding them to the fish’s water. To date, Zon credits the zebrafish for revealing four different drugs that have been used in clinical trials for melanoma, Diamond-Blackfan anemia and adenoid cystic carcinoma, as well as a drug to improve umbilical cord blood transplants.

In this case, Zon’s team used a zebrafish model called Zebrabow, in which different colors serve as ‘barcodes’ of a cell’s identity. In normal zebrafish, blood stem cells have multiple colors, indicating their diversity. Using CRISPR, the team introduced several mutations found in human clonal hematopoiesis in the embryonic fish. They then looked to see if one color of stem cell became dominant — indicating that a rogue population of blood cells had taken over.

“Serine was able to create mosaic mutations so that some of the blood stem cells had the mutation and others didn’t,” Zon says. “We could then ‘compete’ the cells in the fish’s body to see which mutations cause a particular line of cells to take over.”

Suppressing rogue stem cells to curb leukemia

Certain mutations, such as in the asxl1 gene, have indeed led to a single blood stem cell population – and a single cell color – becoming dominant in zebrafish. The researchers then went further and examined which genes turn on different types of blood cells as a result.

Mature white blood cells with mutations that cause clonal hematopoiesis turn on a large number of inflammatory genes. In contrast, mutated blood stem cells turned on anti-inflammatory genes and made anti-inflammatory molecules, protecting themselves from inflammation. When the team knocked out one of these protective genes, nr4a1, that mutated clone lost its fitness advantage and became less dominant.

“We’ve seen a lot of evidence that the bone marrow is really inflamed in patients with clonal hematopoiesis,” Zon says. “But this is one of the first studies to show that there are pathways in stem cells that make them resistant to the inflammation.”

Zon and Avagyan believe that removing that resistance factor could lead to strategies for stopping clonal hematopoiesis. If so, this can stop leukemia at an early stage.

To that end, Zon and colleagues plan to look for a small molecule drug that would target nr4a1 or related anti-inflammatory factors. That would be a first step toward a clinical trial aimed at reducing the risk of leukemia in people with clonal hematopoiesis and high-risk mutations. If the team succeeds, thanks to the zebrafish, the drug would complement the arsenal of drugs the lab has discovered for patients with blood disorders and cancer.

The current study appears today (?) in the journal Science.

Read more about research at Dana-Farber/Boston Children’s

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