Why Helping Cancer Cells “Grow” Could Be the Key to a Cure

Acute myeloid leukemia (AML) is a severe type of cancer in which immature blood cells divide uncontrollably without maturing into functional cells. This leads to an overproduction of abnormal cells that cannot perform the typical functions of mature blood cells, creating a burden on the body’s resources and crowding out healthy cells. Thus, unlike most cancer treatments, where the goal is to kill the cells, most AML therapies aim to nudge these immature cells to “grow up”, or differentiate, into mature non-cancerous blood cells. By encouraging differentiation, these treatments halt uncontrolled cell division and allow these cells to perform normal functions, providing a more effective approach to managing AML than simply trying to kill the cells outright.

One promising approach to induce differentiation involves inhibiting an enzyme called dihydroorotate dehydrogenase (DHODH), which plays a crucial role in producing nucleotides, the building blocks of DNA. Blocking DHODH reduces the availability of nucleotides, which has shown potential to induce cell differentiation. However, the underlying reason why nucleotide depletion promotes differentiation has remained unclear. Understanding this mechanism could help researchers develop more precise treatments, not only for AML but also for other cancers where cells fail to mature.

In a recent study published in Developmental Cell, researchers at the Koch Institute for Integrative Cancer Research at MIT investigated why reducing cellular nucleotide levels triggers differentiation. Using mouse progenitor cells, they set up a controlled system that blocked these cells from developing into mature eosinophils by using a protein called ER-Hox9. This allowed the researchers to isolate and precisely examine the effects of nucleotide depletion on cell development. When they inhibited nucleotide synthesis, the cells experienced 'replication stress'—a state where DNA replication is hindered due to insufficient resources.

To determine if replication stress alone could initiate differentiation, the researchers tested other ways to induce replication stress that did not involve depleting nucleotides. They discovered that these alternative methods, such as inhibiting DNA polymerase, also promoted cell differentiation. This suggested that replication stress itself, rather than nucleotide depletion specifically, plays a crucial role in triggering differentiation. Ultimately, these results underscore replication stress as a potential mechanism through which cells transition from an immature, proliferative state to a mature, differentiated one, offering new insights into cancer therapies that can leverage this pathway.

The study found that, on a molecular level, replication stress activates certain genes and changes the arrangement of DNA within the cell in a way that encourages these cells to mature. These rearrangements, known as chromatin modifications, involve DNA wrapping around proteins that help control which genes are active. This shift happens in part due to changes in how DNA wraps around histones, the proteins that structure DNA, which in turn affects gene activity. By altering which genes are active, replication stress can steer the cell toward a more mature state. Replication stress also appears to weaken the effects of certain proteins that typically block differentiation, allowing the cell to respond more readily to maturation signals. 

The study also showed that the timing of replication stress matters. Inducing replication stress at random points in the cell cycle is not sufficient to prompt differentiation; instead, replication stress is most effective during the S phase, when cells are actively copying their DNA. During this phase, cells seem to be more “open” to switching from an immature to a mature state. Cancer cells in particular are often more sensitive to replication stress in this phase, making it an opportune time to encourage their maturation. This sensitivity could be a valuable target for therapies that aim to induce differentiation in cancer cells.

The implications of these findings are significant for cancer research and treatment. Targeting nucleotide metabolism to induce differentiation could be applied not only to AML but also to other cancers where cell maturation is impaired. By promoting differentiation rather than solely killing cancer cells, this strategy offers the potential for effective, less toxic treatments. Future research could explore combining this strategy with other therapies to enhance its effectiveness, potentially offering a new avenue for cancer therapy that focuses on guiding cells toward a less harmful state.

Original Article:    https://doi.org/10.1016/j.devcel.2024.05.010