polo affects cell fate upon ionizing radiation in Drosophila hematopoietic progenitors by negatively regulating lok

Abstract

In response to ionizing radiation (IR), stem cells undergo cell cycle arrest, senescence, premature differentiation, or cell death. The decision between survival and death is critical during tumorigenesis and effective killing of cancer cells. We used the larval Drosophila lymph gland, a hematopoietic organ, as a model to understand the mechanism for cell fate decisions during stem cell development. The hematopoietic progenitors survived or died via apoptosis when larvae were irradiated in early or late third instar larval (L3) stages, respectively. In late L3 progenitors, the basal level of polo (Drosophila PLK1) was low, enabling IR-induced activation of lok (Drosophila CHK2), which was necessary and sufficient for inducing autophagy and reactive oxygen species (ROS) production resulting in cell death. The high level of polo in early L3 progenitors negatively regulated lok resulting in significantly low or undetectable levels of ROS or autophagy, respectively. The surviving early L3 progenitors underwent cell cycle arrest followed by premature differentiation affected by tefu (Drosophila ATM) and lok mutation. These results provide clues for designing effective therapeutic strategies for cancer. Summary statementWe elucidated the mechanism underlying cell fate decisions during stem cell development in larval Drosophila, which will help develop effective cancer treatment modalities.