HSC senescence upon irradiation

In this issue of Blood, Shao et al report that a side effect of total body irradiation (TBI) is long-term bone marrow injury and thus dysfunctional hematopoiesis caused by the induction of hematopoietic stem cell (HSC) senescence. Interestingly and unexpectedly, however, this happens in a manner independent of the cell-cycle regulators Ink4a and Arf, which play a major role in senescence in other cell systems.¹ 

Treatment of cancer with radiation or chemotherapeutic regimens is a success-story for patients. The refinement of these regimens, in combination with novel targeted therapies, has led to a marked increase in long-term survival, which then renders the question of long-term side effects of such therapies as clinically more relevant.²  So what are long-term consequences and thus likely side effects on hematopoiesis and function of hematopoietic stem cells in response to, for example, radiation treatment? This question usually focuses on the accumulation of DNA damage upon treatment and the likely contribution of DNA mutations resulting from that treatment to therapy-related myelodysplastic syndrome or therapy-related acute myeloid leukemia.^3,4  Conversely, bone marrow suppression, which is still a very common side effect of radiotherapy and still an important cause of death after exposure to a moderate or high dose of TBI, has not been studied in great detail thus far in the clinical setting or animal model systems, especially in the context of long-term outcomes and consequences for stem cells. This is why this novel study of Shao et al is so important.¹ 

Based on previously published data from this laboratory, in which they identified that early hematopoietic progenitors undergo senescence in response to irradiation,⁵  they determined the long-term consequence of TBI on hematopoietic stem cells. They now provide clear evidence that long-term HSCs retain a kind of memory of irradiation damage via induction of premature senescence, which might be the underlying cause of how TBI causes long-term bone marrow suppression. Senescence induction was associated with a significant increase in the production of reactive oxygen species. This aspect of TBI has been somewhat neglected in clinical and basic research. A novel and rather unexpected, but important, additional finding is that contrary to common belief, this senescence is independent of the cell-cycle regulators p16 and Arf, proteins prominently involved in replicative senescence and DNA damage checkpoint activation, as well as stem cell aging.^1,6  These results thus imply that changes in these cell-cycle regulators are rather correlative and not primarily causative for regulation of hematopoiesis in response to TBI. This manuscript thus greatly extends our current knowledge on the long-term effects of DNA damage on hematopoiesis and hematopoietic stem cells.

What do these results mean for the clinic? Because of the success of DNA-damaging treatments in various cancer settings, and because of the demographic changes in our society, we will most likely see more patients who have received such therapies. One might need to be more vigilant with respect to undetected bone marrow injury in such patients.

Where do we go from here in research? One question always linked to DNA-damaging regimens is the question on DNA mutations in response to the damage. Is senescence and the following reduced clonogenicity protecting the hematopoietic system from acquiring a set of actively cycling but mutated stem cells? Does radiation damage support therapy, either via high levels of cytokines or via radioprotective or radiomitigating treatments, have either a beneficial or a rather detrimental effect with respect to inducing senescence and thus long-term support of hematopoiesis?^7,8  And ultimately, which cell-cycle control pathways do stem cells use to react to radiation damage and to regulate DNA-damage outcomes? And might there be a way to revert the long-term senescence associated with TBI?