Two recent publications from CU Cancer Center members offer insight into the role of chronic inflammation in the development and progression of leukemia.Both papers were co-authored by Eric Pietras (Pietras, PhD), CU Cancer Center member and assistant Professor in the CU School of Medicine Division of Hematology. James DeGregori (Pietras), deputy director of CU Cancer Center and professor at the Department of Biochemistry and Molecular Genetics.These papers support the theory of adaptive-oncogenesis, which DeGregori developed. This theory states that chronic inflammation, such as inflammation caused by aging or chronic disease, reduces the fitness and ability of normal cells. It also creates space for cancer-causing mutations to proliferate.Previous understandings are not enoughThe first paper, "PU.1 enforces queescence and limits hematopoietic cell expansion during inflammatory stress," is Pietras' laboratory technician James Chavez, B.S. This paper examines the effects of inflammation on transcription factor PU.1 as well as its impact on the production hematopoietic and hematopoietic cells (HSCs), which are immature bone marrow cells that can become blood cells.Pietras stated that this research challenged his understanding of inflammation and HSCs.He explains that introducing a proinflammatory cytokine such as Interleukin 1 (IL-1) would increase hematopoietic stem cell proliferation. "When there is inflammation, the body usually interprets it to be a signal to make more white blood cells to fight an infection or injury."Pietras and his colleagues discovered that IL-1 caused genes to be turned off, rather than on, when creating additional hematopoietic cells. This included genes that regulate the synthesis proteins, which is the most important building block of new cells.The team discovered that a transcription factor called "PU.1" suppresses the expression of protein synthesis genes in HSCs when there is inflammation.Pietras states, "That made us wonder if we could get rid of PU.1." They used genetic mouse models to either reduce or eliminate PU.1 from the HSCs. Pietras had predicted that HSC proliferation and expansion would occur if PU.1 was reduced or eliminated.Pietras states that "our findings point to an intriguing mechanism for how inflammation may trigger differences in cell fitness, when normal HSCs must compete with HSCs harbouring oncogenic mutations known to disable or decrease PU.1". Pietras says that HSCs with PU.1 deficiencies behave like normal cells, as long as there is no inflammation. It's like lighting a match. Because there is no mechanism to stop their protein synthesis, the HSCs without PU.1 growth expand. This can lead to uncontrolled growth in the PU.1-deficient HSCs, which could eventually lead to leukemia (a form of blood cancer).Pietras said that his findings were contrary to his prior understanding of inflammation. He says, "I believe some of the most important science is that which disproves you own ideas and dogmas."Chronic inflammation and agingDeGregori and Pietras co-authored the second paper, "Chronic Interleukin-1 Exposure Triggers Selection for Cebpa Knockout Multipotent Hematopoietic Progenitors". This paper also examines the effects of IL-1, a proinflammatory cytokine, on hematopoietic stem cells and progenitor cell (HSPCs). Kelly Higa was the primary author of this study, a student in CU’s MD/PhD program that is co-mentored and guided by Pietras and DeGregori.DeGregori states that one of the main goals of the study was to understand how blood stem cells produce mature blood cells. This is especially important in the context of chronic inflammation.This was done in mice models, injecting them with IL-1 to mimic an infection and causing inflammation. This caused a shift in blood cell production to make granulocytes. Granulocytes are a type white blood cell that aids the immune system fight infection.The team found that inflammation can alter selection in the HPCs towards oncogenic mutations in the Cebpa gene. This is a key transcription factor that makes mature myeloid cells, such as granulocytes. It is often found in leukemia.DeGregori states that for every positive process in your body such as fighting infection there could be negative reactions that can create risk. "And we believe inflammation can pose a risk, especially if it is a chronic condition."Chronic infections like colitis and arthritis are two examples of conditions that can cause long-term inflammation. DeGregori claims that inflammation is most common in old age.He explains that many people become chronically irritable as we age. While not everyone experiences the same amount of inflammation, higher levels tend to correlate with worse outcomes. Our data suggests that older age and the inflammation that comes with it could be contributing to increased rates of leukemia in elderly patients, especially acute myeloid leukemia.DeGregori claims that this finding is "counterintuitive" to what most people believe, which is the fact that cancer-causing mutations cause the proliferation of cancer cells. He says, "But we're saying that the cancer-causing mutation does not do anything by itself." "There must be a selective force. In this instance, it is inflammation."Inflammation: friend or foe?Both Pietras and DeGregori stress, however, that it isn't as simple as eliminating inflammation.DeGregori states that inflammation is crucial for survival of infections. "Inflammation is crucial for survival of infection. We evolved it as a way to prevent the possibility of dying from infection over time. We have shown that chronic inflammation can promote selection for oncogenic events such as the inhibition of Cebpa.Pietras says that inflammation is not always an enemy. It is necessary to fight pathogens and repair tissues. When inflammation becomes dangerous, it can become an enemy.Pietras states that the next step is to apply the findings to human biology.Pietras states that there are several implications for the research. One is that we are learning more about the time and place where stem cells acquire mutations, and how inflammation can affect the ability of these mutant HSCs eventually to initiate leukemia. This tells us that we might be able reduce the risk of developing blood cancer if we intervene early enough.Researchers say that the research also suggests that both prevention measures for people at greater risk for developing cancer as well as treatments for those already diagnosed with it could be improved by treating chronic inflammation and maintaining immune system function.DeGregori states, "We don’t want to reduce someone’s risk of developing leukemia but at the sametime increase their chance of dying from infection." "But, the more we know about it, the easier we can find that happy balance.###
