TY - JOUR
T1 - Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression
AU - Magee, Jeffrey A.
AU - Ikenoue, Tsuneo
AU - Nakada, Daisuke
AU - Lee, Jae Y.
AU - Guan, Kun Liang
AU - Morrison, Sean J.
N1 - Funding Information:
This work was supported by the National Institute on Aging (R37 AG024945), the Howard Hughes Medical Institute, and the Cancer Prevention and Research Institute of Texas. J.A.M. was supported by a grant from the Pediatric Scientist Development Program of the Association of Medical School Pediatric Department Chairs and the National Institute of Child Health and Human Development. Torin1 was a gift of Nathaniel Gray (Harvard University). J.A.M. performed all experiments and participated in the design and interpretation of all experiments. T.I. and K.L.G. generated the Rictor fl allele. D.N. backcrossed the Rictor fl allele onto a C57BL/6Ka-Thy-1.1 background and assisted with reconstitution experiments. J.Y.L. assisted with the analysis of reconstitution experiments. S.J.M. participated in the design and interpretation of all experiments and wrote the paper with J.A.M.
PY - 2012/9/7
Y1 - 2012/9/7
N2 - Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.
AB - Pten deletion from adult mouse hematopoietic cells activates the PI3-kinase pathway, inducing hematopoietic stem cell (HSC) proliferation, HSC depletion, and leukemogenesis. Pten is also mutated in human leukemias, but rarely in early childhood leukemias. We hypothesized that this reflects developmental changes in PI3-kinase pathway regulation. Here we show that Rictor deletion prevents leukemogenesis and HSC depletion after Pten deletion in adult mice, implicating mTORC2 activation in these processes. However, Rictor deletion had little effect on the function of normal HSCs. Moreover, Pten deletion from neonatal HSCs did not activate the PI3-kinase pathway or promote HSC proliferation, HSC depletion, or leukemogenesis. Pten is therefore required in adult, but not neonatal, HSCs to negatively regulate mTORC2 signaling. This demonstrates that some critical tumor suppressor mechanisms in adult cells are not required by neonatal cells. Developmental changes in key signaling pathways therefore confer temporal changes upon stem cell self-renewal and tumor suppressor mechanisms.
UR - http://www.scopus.com/inward/record.url?scp=84866064701&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2012.05.026
DO - 10.1016/j.stem.2012.05.026
M3 - Article
C2 - 22958933
AN - SCOPUS:84866064701
SN - 1934-5909
VL - 11
SP - 415
EP - 428
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 3
ER -