Many cytokines and chemokines that are important for hematopoiesis activate the PI3K signaling pathway. Because this pathway is frequently mutated and activated in cancer, PI3K inhibitors have been developed for the treatment of several malignancies and are now being tested in the clinic in combination with chemotherapy. However, the role of PI3K in adult hematopoietic stem cells (HSCs), particularly during hematopoietic stress, is still unclear. We previously showed that the individual PI3K catalytic isoforms p110α and p110β have dispensable roles in HSC function, suggesting redundancy between PI3K isoforms in HSCs. We now demonstrate that simultaneous deletion of p110α and p110δ in double-knockout (DKO) HSCs uncovers their redundant requirement in HSC cycling after 5-fluorouracil (5-FU) chemotherapy administration. In contrast, DKO HSCs were still able to exit quiescence in response to other stress stimuli, such as LPS. We found that DKO HSCs and progenitors had impaired sensing of inflammatory signals ex vivo, and that levels of IL-1β and MIG were higher in the bone marrow (BM) after LPS than after 5-FU administration. Furthermore, exogenous in vivo administration of IL-1β could induce cell cycle entry of DKO HSCs. Our findings have clinical implications for the use of PI3K inhibitors in combination with chemotherapy.
Shayda Hemmati, Taneisha Sinclair, Meng Tong, Boris Bartholdy, Rachel O. Okabe, Kristina Ames, Leanne Ostrodka, Tamanna Haque, Imit Kaur, Taylor S. Mills, Anupriya Agarwal, Eric M. Pietras, Jean J. Zhao, Thomas M. Roberts, Kira Gritsman
Usage data is cumulative from May 2019 through October 2019.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.