Chronic Inflammation Can Serve as A Key Factor in The Development of Leukemia, Other Blood Cancers

Two studies by the University of Colorado Cancer Center provided an analysis for the theory of adaptive oncogenesis.

In 2 recent studies by the University of Colorado (CU) Cancer Center in Aurora, Colorado, there are many insights into how chronic inflammation can serve as the key to developing leukemia and other blood cancers, according to an author at the university.

Both papers provided an analysis for the theory of adaptive oncogenesis, which was developed by corresponding study author James DeGregori, PhD, deputy director of the CU Cancer Center. The theory hypothesizes that chronic inflammation, such as inflammation associated with aging or chronic disease, reduces the fitness of normal cells, stopping their ability to reproduce and creating space for cells with cancer-causing mutations to proliferate.

The first paper, titled “PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress,” takes a look at the effect of inflammation on the transcription factor PU.1 and its effect on the production of hematopoietic stem cells (HSCs), or the immature cells found in the bone marrow that can turn into blood cells, according to the study author James Chavez, BS.

Second corresponding author Eric Pietras, PhD, CU Cancer Center Member, said the research from Chavez challenged his previous understanding of how inflammation impacts HSCs.

“We thought that introducing a proinflammatory cytokine like Interleukin (IL)-1 would make hematopoietic stem cells proliferate, because when you have inflammation, the body typically interprets it as a signal to produce more white blood cells to fight off an infection or injury,” Pietras said, in a CU interview.

However, he and his team discovered that in the presence of IL-1, genes that control the creation of additional hematopoietic stem cells were turned off rather than on, specifically genes related to the synthesis of proteins, were the key of building new cells. “I think some of the best science is that which disproves your own notions and dogmas,” Pietras said in the CU interview.

The team ended up finding a transcription factor called PU.1 that represses protein synthesis genes in HSCs during periods of inflammation.

“That made us wonder what would happen if we got rid of PU.1,” Pietras said in the CU interview. He and his team used genetic mouse models that reduced the amount of PU.1 in the HSCs or remove it altogether, uncovering that when PU.1 is reduced or removed, inflammation caused by the introduction of IL-1 triggers the proliferation and expansion of HSCs.

“Our findings point to an interesting mechanism for how inflammation can trigger differences in cell fitness when normal HSCs have to compete with HSCs harboring oncogenic mutations that are known to disable or reduce PU.1,” Pietras said in the CU interview. “In this case, those PU.1- deficient HSCs act like normal cells as long as there's no inflammation. But as soon as you trigger an inflammatory response, it's like throwing gasoline on a fire. The HSCs with loss of PU.1 expand because there is no longer a mechanism to turn their protein synthesis off. And when that happens, you get uncontrolled growth of the PU.1-deficient hematopoietic stem cells, which can eventually lead to leukemia, a type of blood cancer.”

The second paper, titled “Chronic interleukin-1 exposure triggers selection for Cebpa-knockout multipotent hematopoietic progenitors,” co-led by DeGregori and Pietras, looks at the impact of the proinflammatory cytokine IL-1 on hematopoietic stem and progenitor cells (HSPCs).

One of the primary goals, according to DeGregori, was to better understand the factors that determine what kind of mature blood cells are produced from our blood stem cells, or the HSPCs, in response to chronic inflammation. Mouse models were studied by injecting with IL-1 to copy an infection and cause inflammation. This action impacted blood cell production towards making granulocytes, which is a type of white blood cell that helps the immune system fight infections, according to the study authors.

The team also found that inflammation seemed to alter selection in the HSPCs toward oncogenic mutations of the Cebpa gene that are often found in leukemia.

"Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly,” DeGregori said in the CU interview. “For every good process that happens in your body, such as fighting infection, there can also be adverse reactions that create risk. And we think inflammation creates some level of risk, particularly if it's a chronic situation.”

DeGregori added that the most widespread cause of inflammation is old age, and examples of conditions that could cause long-term inflammation include arthritis and chronic infections, such as colitis.

"When we get old, many of us become chronically inflamed,” DeGregori said in the CU interview. “Not everyone experiences the same level of inflammation, but higher inflammation tends to coincide with worse outcomes for people. Our data would suggest that old age, and the inflammation associated with it, could contribute to the increased leukemia rates that occur in the elderly, particularly acute myeloid leukemia (AML).”

DeGregori and Pietras note that solving this issue is more complicated than wiping out inflammation altogether.

“Inflammation is critically important for surviving infections,” DeGregori said in the CU interview. “Over evolutionary time, dying from infection was a major risk, so we evolved inflammation as a mechanism to avoid that. On the other hand, we've shown that chronic inflammation could promote selection for oncogenic events, such as through inhibition of Cebpa.”

According to Pietras, the next step is to apply these findings to human biology.

“I think there are a few different implications for the work,” Pietras said in the CU interview. “One is that we're learning more about when and where stem cells first gain mutations and the extent to which inflammation can impact the capacity of these mutant HSCs to eventually initiate leukemia. What this tells us is that if we can intervene at an early stage, we may be able to reduce the risk of getting blood cancer.”

The studies helped to show that both preventive measures for those at higher risk of developing cancer and treatments for those who are already diagnosed could potentially be improved by addressing “bad” inflammation while maintaining the immune system’s ability to function, according to study authors.

"We don't want to limit someone's risk of getting leukemia and at the same time increase their risk of dying from an infection,” DeGregori said in the CU interview. “But the more we learn about it, the better we might get at finding that happy balance.”

REFERENCE

Gleaton V. Two Studies by CU Cancer Center Researchers Explore Link Between Inflammation and Leukemia. University of Colorado Cancer Center. Published June 28, 2021. Accessed July 1, 2021. https://news.cuanschutz.edu/cancer-center/two-studies-inflammation-and-leukemia