Not all cells carrying oncogenes transform into cancer, which leads scientists to question what discriminates a cell to transformed and others to remain normal. This process has been well-described for some solid tumors, where genetic lesions, or epigenetic alterations, are thought to be the cause. But not in other cancers, with low mutational loads such as those of hematopoietic origin, are unknown. The researchers wanted to determine the cellular traits that contribute to the acquisition of de novo malignancy in blood cancer.
"Many people with cancer-causing genes remain healthy for many, many years,'' said senior author Shangqin Guo, assistant professor of cell biology and a researcher at the Yale Stem Cell Center. "So, in these cases, you have to wonder whether the dogma 'mutations cause cancer' is the complete truth."
The research focused on granulocyte-macrophage progenitors (GMPs) that allow mixed lineage leukemia (MLL) fusion oncogene-mediated transformations. They observed that the progenitors produced two types of progeny: differentiated cells, or malignant cells that could develop into lethal acute myeloid leukemia (AML). AML carries the lowest number of mutations among known human cancers.
They introduced a leukemia-causing mutation, MLL-AF9, into mice genomes and tracked individual blood cells for indicators of transformation. While the great majority of cells remained normal, the few cells that divided most quickly almost always became malignant. The rapidly proliferating, immature myeloid progenitor cell state initiates transformation when this cell state is perpetuated by MLL-AF9 expression, fulfilling the functional definition of malignancy.
"When a normal cell that divides quickly meets MLL-AF9, this combination creates a monster cell that is stuck in a state of perpetual fast division," Guo said. "Their more slowly cycling counterparts remain normal and do not display the malignant cancer traits, even in the presence of cancer-causing mutations."
Certain cell states, such as infection can trigger the proliferation of rapidly-dividing cells to combat pathogens, but which could, as this research shows, open the door to cancer. Alternatively, stem cells experience functional decline due to again, which requires increased proliferation of healthy stems cells to repair additional damage. The researchers suggest that this increase could also explain why people become more susceptible to cancer as they age.
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