Temporal Changes in PTEN and mTORC2 Regulation of Hematopoietic Stem Cell Self-Renewal and Leukemia Suppression

Abstract

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.

Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis

“…Activation of mTorc2 by PI3K leads to mTor-catalyzed phosphorylation and activation of Akt on S473 (Akt-S473) 20 . Mutation of the mTorc2-specific component Rictor reverses the effects of Pten mutation in leukaemia 21 , demonstrating that the mTorc2/Akt-S473 pathway is an important downstream target of Pten (via PI3K) 4 . Consistent with Pten expression, Akt-S473 was absent in normal lung, AAH and adenomas (Fig.…”

“…Pten mutation has little effect on hematopoietic stem cell differentiation before adulthood, but Pten becomes a critical tumour suppressor of leukaemia in adults 21 . Because of the linkage between ZEB1 and Pten we show here, it is of note that ZEB1 expression is closely linked to cell proliferation during development, and it is therefore downregulated in most postmitotic adult cells 10 .…”

Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells

“…In a mouse model, deletion of Pten during hematopoiesis demonstrated that Pten is critical for suppressing the development of leukemia (7)(8)(9). Furthermore, studies using Raptor-or Rictordeficient mice revealed that activation of mTORC1 or -2 is required for the leukemogenesis evoked by Pten loss (10,11). However, the involvement of mTORC1 in leukemogenesis associated with other oncogenic signals, such as Ras, is not well understood.…”

Fetal hematopoietic stem cells are making waves

“…Altogether, this work suggested that Flk2 expression was associated with loss of self-renewal potential and initiation of robust proliferation in adult hematopoietic progenitors (10)(11)(12)14). During fetal hematopoiesis, however, activity of the FlkSwitch system correlated very differently with HSC phenotype and transplantability as compared to adult hematopoiesis, giving rise to the identification of the fetal drHSCs recently reported by Beaudin and coworkers (10 (16,17). Although transplantation assays have been instrumental to rigorously and prospectively define HSCs, findings by Beaudin and coworkers highlight the fact that transplantation into irradiated recipients remains an experimental assay, and that behavior of a given population of progenitors after transplantation (e.g., long-term reconstitution from drHSCs) does not necessarily match their in vivo activity (e.g., spontaneous disappearance of these cells in physiological conditions).…”