Box 6.

Promyelocytic Leukemia Protein (PML).

PML is a protein that is active in the cell nucleus by the formation of nuclear bodies, the so-called PML-NBs. 112 PML stabilizes the genome and interacts with at least 120 different cellular proteins by physical association with PML-NBs. It is considered to be a tumor suppressor protein because it downregulates cell proliferation, whereas its inactivation and downregulation are associated with cancer. 112 PML induces quiescence of HSCs and NSCs and it stimulates their FAO and PPAR signaling.113,114 For the same reason, it is also important for LSCs and GSCs.86,115 Therefore, PML may be an important player in the protection of LSCs and GSCs in their niches and thus, PML may be a tumor suppressor protein that can also promote cancer as FOXO3 does.114,116 Therapeutic inhibition of PML eradicates LSCs. 116 Furthermore, PML affects the tumor microenvironment as it inhibits angiogenesis via inhibition of mTOR. 117

Abbreviations: FAO, fatty acid oxidation; PPAR, peroxisome proliferator-activated receptor; FOXO3, forkhead box O3; HSCs, hematopoietic stem cells; NSCs, neural stem cells; LSCs, leukemic stem cells; GSCs, glioblastoma stem cells; mTOR, mammalian target of rapamycin.