CD244 Maintains The Proliferationability Of Leukemia Initiating Cells Through SHP-2/p27^kip1 Signaling

Targeting leukemia initiating cells(LICs)is considered to be an effective way to cure leukemia,for which it is critical to identify novel therapeutic targets.Herein,we demonstrate that CD244,which is initially reported as a key regulator for NK cells,is highly expressed on both mouse and human LICs.Upon CD244 knockdown,human leukemia cell lines and primary leukemia cells have markedlyimpaired proliferation abilitiesboth in vitro and in vivo.Interestingly,the repopulation ability of human hematopoietic stem cells(HSCs)is not impaired upon CD244 knockdown.Using a MLL-AF9 induced murineacute myeloid leukemia model,we show that leukemogenesis is dramatically delayed upon CD244 deletion,together with remarkably reduced Mac1+/c-Kit+ leukemia cells(enriched for LICs).Mechanistically,we reveal that CD244 is associated with c-Kit and p27 except for SHP-2 as previously reported.CD244 cooperates with c-Kit to activate SHP-2 signaling to dephosphorylate p27 and maintain its stability to promote leukemia development.Collectively,we provide intriguingevidences that the surface immune molecule CD244 plays an important role in the maintenance of stemness of LICs,but not in HSCs.CD244 may be served as a novel therapeutic target for the treatment of acute myeloid leukemia.Herein,we show that branched-chain amino acids(BCAAs),is important for the stemness maintenance of HSCs.As the essential regulator of the degradation of BCAAs,PP2 Cm can maintain the quiescence of HSCs through controlling the ubiquitination degradation of both Meis1 and p21,which is mediated by the E3 ubiquitin ligase CDC20.Our study will open a new avenue to understand how nutrient signalings maintain the metabolism and stemness of HSCs.