Leukemia, or blood cancer, involves pathological alterations in the body’s hematopoietic system. In acute myeloid leukemia, it is specifically the bone marrow that is affected. In a healthy body, different blood cells, which perform different functions in the blood, are formed from stem cells and what is referred to as progenitor cells in the bone marrow. The disease is triggered by pathological alterations of bone marrow cells, where these cells do not die when they are damaged. Now, a study from researchers at the Technical University of Munich (TUM) identifies a previously unknown molecular signaling pathway for self-destruction that is suppressed in leukemia cells. The team state that their study also highlights the fact that it is important to understand cells have different ways of self-destructing. The opensource study is published in the journal Cancer Cell.
Previous studies show that a genetic mutation can lead to alterations in stem cells and progenitor cells and turn them into leukemia-initiating cells, which are referred to as LICs for short. Like healthy progenitor cells, LICs multiply in the bone marrow. Research on why cancer cells survive longer than they should, has mainly focused on a process called apoptosis. However, the fact that inflammatory processes occur in LICs pointed the lab in a different direction, another way to initiate cell death is through what is referred to as necroptosis. Whereas, in apoptosis, a cell shrinks in a coordinated fashion, in necroptosis, a sudden destruction occurs, which releases the contents of the dying cell along with numerous messenger substances. Studies show that LICs manage to grow and proliferate despite the inflammation and damage. The current study investiagates the molecular causes of this resistance to necroptosis.
The current study uses cell cultures to show that leukemia takes a particularly severe course when a protein called RIPK3 is blocked inside LICs, which in turn blocks necroptosis. The researchers explain that necroptosis is triggered by the activation of RIPK3, which subsequently initiates processes within the cell that lead to its death. Results show that this leads to the cancer cells surviving particularly long, accompanied by their strong division and conversion to functionless blood cells. Data findings show that particularly aggressive cancer cells have the capacity to block RIPK3.
Results show that inducing cell death in a LIC by means of necroptosis has repercussions which also affect neighbouring leukemia cells. The team state that the inflammatory stimuli triggered by the substances released during necroptosis are significantly stronger than the processes caused by the mutation in the FLT3 gene in a LIC. They go on to add that this inflammation has positive effects on the area surrounding the cell; induced by the messenger substances, neighbouring leukemia cells begin to mature similar to healthy cells, leading to a less aggressive progression of leukemia.
The team surmise that their findings show with cell-death blocked, apoptosis, too, is neutralized in many cancer cells, with individual LICs managing to survive and proliferate even after chemotherapy or radiotherapy. For the future, the researchers state that the new findings on the impact of the RIPK3 signaling pathway and messenger substances could open up new options for the treatment of leukemia. They conclude that if it were possible to artificially reproduce the effect of RIPK3 using medication, the global medical community could launch a targeted attack on leukemia cells.
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