Oncology Mutated Cells Can Significantly Influence the Development of Blood Cancers

A new study has revealed that even a few mutated cells can significantly impact the entire blood-forming system. This new finding could potentially change the way doctors treat their cancer patients.

Rhode Island/USA – A team of researchers led by a Brown University cancer biologist found that when they introduced mutated blood cancer cells into mice and tracked them over time, the cancer cells affected not only non-mutated cells, but also the entire blood-forming system. In a federally funded study published in the American Society of Hematology journal Blood, the team showed that non-mutated blood-producing cells were impacted significantly by the presence of the cancer cells.

“Even low numbers of mutated cancer cells profoundly affected the blood-producing system and bone homeostasis,” said senior study author Patrycja Dubielecka, an associate professor at the Warren Alpert Medical School of Brown University and a co-leader of the Cancer Biology Program at Brown’s Legorreta Cancer Center. “We realized that there would be some impact of introducing the cancer cells, but the extent of how profoundly both the blood-forming system and bone biology have changed was absolutely stunning to see.”

The findings have implications for how blood cancers are treated, said Dubielecka, who is also the director of translational hematology at Rhode Island Hospital.

“Even if you eradicate the mutated clone, the system is so dramatically changed that the recovery is going to be very difficult — unless you understand the molecular basis of changes within the bystander non-mutated cells so you can potentially try to reverse them,” she said.

Dubielecka explained that over the past decade, cancer researchers have focused on the microenvironment of cancer cells, studying how mutated cells affect the other healthy cells in the vicinity. The challenge for researchers has become how to model this type of biological situation to understand what is happening at the systemic level.

Lead study author Dennis Bonal, a postdoctoral fellow at Brown based in Dubielecka’s lab, created a mouse model with molecular tags where introduced cancer cells can be easily detected through standard laboratory methods.

“This way we have the capacity to track not only the cancer cells we are introducing, but also the recipient cells,” Dubielecka said.

The team started by introducing small amounts of cancer cells into several cohorts of mice and gradually increased the amounts. They tracked the animals for eight months as they developed age-related malignancies and systemic pathologies, including bone loss. According to Dubielecka, this was similar to the human physiological setting in which cancer develops and expands over time.

“We wanted to make sure we are creating a model that is close to the course of onset of this type of cancer in humans,” she said.

They found that the cancer cells with a certain type of gene mutation called Jak2 resulted in a significant level of molecular mimicry between JAK2-mutated and non-mutated bystander cells.

Currently, when these types of malignancies are found early in relatively young human patients, the typical approach involves “watchful waiting,” Dubielecka said. Most current treatments are limited in terms of intervention scope — physicians do not tend to be aggressive towards eradicating the cloned cells early, typically focusing instead on helping patients managing symptoms.

“Based on our findings, this strategy needs to be revised,” Dubielecka said. “The moment that mutated blood cancer cells are detected in the system, the effort should really be directed toward shrinking the frequency of this clone that carries the mutation — because we know that over time this clone will induce significant damaging changes that will be difficult or even impossible to reverse.”

Now that the team has identified the scope of systemic changes induced by the mutated clone, they plan to further study the nearby non-mutated bystander cells to better understand and determine how to reverse the molecular changes affecting these cells. The study was funded by the National Cancer Institute (R01CA218079) and the National Institute of General Medicine (P20GM119943, P30GM145500).

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