Distinct and Dynamic Requirements for mTOR Signaling in Hematopoiesis and Leukemogenesis
2012; Elsevier BV; Volume: 11; Issue: 3 Linguagem: Inglês
10.1016/j.stem.2012.08.007
ISSN1934-5909
Autores Tópico(s)Mast cells and histamine
ResumoSignaling involving PI3K and AKT regulates cell growth, partly through the mTOR kinase complexes 1 and 2. In this issue of Cell Stem Cell, Kalaitzidis et al. and Magee et al. reveal unique requirements for mTORC1 and mTORC2 signaling during blood development and leukemogenesis induced by loss of PTEN. Signaling involving PI3K and AKT regulates cell growth, partly through the mTOR kinase complexes 1 and 2. In this issue of Cell Stem Cell, Kalaitzidis et al. and Magee et al. reveal unique requirements for mTORC1 and mTORC2 signaling during blood development and leukemogenesis induced by loss of PTEN. Normal blood development depends upon the regulated renewal and expansion of hematopoietic stem cells (HSCs), which give rise to progressively differentiated cell types that ultimately constitute circulating blood. Thus, aberrant regulation of the signaling pathways that underlie normal HSC renewal and differentiation is one of the pathogenic hallmarks of human leukemias. In particular, members of the PI3K family of lipid kinases act to catalyze the production of phosphatidylinositol triphosphate (PIP3) in response to extracellular ligands and cell surface receptors, including those involved in blood development (Vanhaesebroeck et al., 2010Vanhaesebroeck B. Guillermet-Guibert J. Graupera M. Bilanges B. Nat. Rev. Mol. Cell Biol. 2010; 11: 329-341Crossref PubMed Scopus (1265) Google Scholar). In the human leukemias, including T cell acute lymphoblastic leukemia (T-ALL), PI3K signaling is frequently activated as a result of loss-of-function mutations of the phosphatase PTEN, which normally antagonizes PI3K (Gutierrez et al., 2009Gutierrez A. Sanda T. Grebliunaite R. Carracedo A. Salmena L. Ahn Y. Dahlberg S. Neuberg D. Moreau L.A. Winter S.S. et al.Blood. 2009; 114: 647-650Crossref PubMed Scopus (354) Google Scholar; Song et al., 2012Song M.S. Salmena L. Pandolfi P.P. Nat. Rev. Mol. Cell Biol. 2012; 13: 283-296Crossref PubMed Scopus (434) Google Scholar). Production of PIP3 activates AKT, as well as numerous downstream signaling mediators such as the mTOR kinase, which is a key component of two complexes, mTORC1 and mTORC2 (Laplante and Sabatini, 2012Laplante M. Sabatini D.M. Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (6136) Google Scholar). These complexes contain several shared proteins, as well as unique components such as the substrate recruitment factors Raptor and Rictor, which can be used to discriminate between mTORC1 and mTORC2, respectively. Activation of PI3K-AKT signaling in mouse blood cells, due to either the loss of PTEN or mutational activation of AKT, can induce HSC proliferation and depletion, and can lead to T-ALL (Kharas et al., 2010Kharas M.G. Okabe R. Ganis J.J. Gozo M. Khandan T. Paktinat M. Gilliland D.G. Gritsman K. Blood. 2010; 115: 1406-1415Crossref PubMed Scopus (220) Google Scholar; Yilmaz et al., 2006Yilmaz O.H. Valdez R. Theisen B.K. Guo W. Ferguson D.O. Wu H. Morrison S.J. Nature. 2006; 441: 475-482Crossref PubMed Scopus (1118) Google Scholar; Zhang et al., 2006Zhang J. Grindley J.C. Yin T. Jayasinghe S. He X.C. Ross J.T. Haug J.S. Rupp D. Porter-Westpfahl K.S. Wiedemann L.M. et al.Nature. 2006; 441: 518-522Crossref PubMed Scopus (677) Google Scholar). However, the individual contributions of mTORC1 and mTORC2 to normal blood development and the molecular pathogenesis of T-ALL induced by PTEN loss are not well understood. In this issue of Cell Stem Cell, Kalaitzidis et al. and Magee et al. now reveal the distinct roles of mTORC1 and mTORC2 during normal hematopoiesis and leukemogenesis (Kalaitzidis et al., 2012Kalaitzidis D. Sykes S.M. Wang Z. Punt N. Tang Y. Ragu C. Sinha A.U. Lane S.W. Souza A.L. Clish C.B. et al.Cell Stem Cell. 2012; 11 (this issue): 429-438Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar; Magee et al., 2012Magee J.A. Ikenoue T. Nakada D. Lee J.Y. Guan K.-L. Morrison S.J. Cell Stem Cell. 2012; 11 (this issue): 415-428Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar; Figure 1). Through conditional inactivation of Raptor and Rictor in genetically engineered mice, these authors identify the unique requirements for Raptor/mTORC1 and Rictor/mTORC2 for HSC function and PTEN loss-induced leukemogenesis. The study by Kalatitzidis et al. used conditional knockout mice for Raptor, Rictor, or both factors to compare their roles in HSC function. They found a nonredundant requirement for Raptor in HSC regeneration and also defined a role for Raptor in PTEN loss-induced leukemogenesis. Magee et al. studied mice with a conditional deletion of Rictor and found that while loss of Rictor/mTORC2 had little effect on normal HSC function, Rictor-dependent mTORC2 signaling is required for leukemogenesis in adult, but not neonatal, HSCs lacking PTEN. Both groups found that deletion of Rictor leads to reduced mTORC2 activity, as judged by AKT S473 phosphorylation, with no effects on the steady-state proliferation of mouse HSCs, and only small reductions in peripheral white blood counts. Rictor-deficient cells were also able to completely reconstitute irradiated mice, albeit with slower kinetics than Rictor-proficient controls. In contrast to mice with conditional inactivation of Rictor/mTORC2, mice with deletion of Raptor and consequent inactivation of mTORC1 developed profound pancytopenia (Kalaitzidis et al., 2012Kalaitzidis D. Sykes S.M. Wang Z. Punt N. Tang Y. Ragu C. Sinha A.U. Lane S.W. Souza A.L. Clish C.B. et al.Cell Stem Cell. 2012; 11 (this issue): 429-438Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). These blood count changes were associated with nearly complete loss of HSC regenerative capacity, as determined from careful chimerism and transplantation experiments. Hence, normal hematopoiesis and HSC regeneration appear to be primarily regulated by the Raptor-dependent activities of mTORC1. Loss of PTEN in HSCs, with consequent activation of PI3K-AKT signaling, leads to increased HSC cycling with a deficiency in self-renewal and eventual HSC depletion. These PTEN-deficient HSCs give rise to abnormalities in thymocyte progenitors, culminating in the development of T-ALL. mTORC2 appears to be essential for the effects of PTEN loss on both normal HSC self-renewal and leukemogenesis, because deletion of Rictor normalized HSC proliferation and blocked T-ALL in the PTEN null background (Magee et al., 2012Magee J.A. Ikenoue T. Nakada D. Lee J.Y. Guan K.-L. Morrison S.J. Cell Stem Cell. 2012; 11 (this issue): 415-428Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). Deletion of Raptor also significantly reduced the incidence of T-ALL in PTEN-deficient animals, indicating a nonredundant requirement for both mTORC1 and mTORC2 activities in leukemic transformation induced by PTEN loss (Kalaitzidis et al., 2012Kalaitzidis D. Sykes S.M. Wang Z. Punt N. Tang Y. Ragu C. Sinha A.U. Lane S.W. Souza A.L. Clish C.B. et al.Cell Stem Cell. 2012; 11 (this issue): 429-438Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Importantly, the studies by Kalaitzidis et al. and Magee et al. establish a potential therapeutic window for interfering with leukemogenic PI3K-AKT signaling by using specific blockade of Rictor-dependent mTORC2 activities, which does not appear to have significant effects on steady-state and long-term regenerative hematopoiesis in mice, yet substantially impedes the development of T-ALL. Therapeutic blockade of Raptor-dependent mTORC1 activities in T-ALL driven by PTEN loss is likely to be more challenging, as mTORC1 function is required to sustain normal hematopoiesis. Interestingly, HSCs from neonatal mice appear to resist the effects of PTEN loss on cell proliferation, and do not give rise to T-ALL (Magee et al., 2012Magee J.A. Ikenoue T. Nakada D. Lee J.Y. Guan K.-L. Morrison S.J. Cell Stem Cell. 2012; 11 (this issue): 415-428Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar). PTEN-deficient HSCs from neonatal mice show reduced AKT activation as compared to their adult counterparts, suggesting that they are endowed with activities that limit the production of PIP3 and/or activation of AKT. Given that mTORC2 is required for PTEN loss-induced leukemogenesis and that mTORC2 can activate AKT, the resistance of neonatal HSCs to the effects of PTEN loss suggests the testable hypothesis that mTORC2 may be physiologically suppressed during neonatal development. Future studies to elucidate the mechanisms underlying such suppression, or perhaps alternative explanations for lower levels of AKT activation in both wild-type and PTEN-deficient neonatal hematopoietic cells, may permit the eventual "reprogramming" of hematopoietic cells to a state of PI3K nonresponsiveness, which could then be exploited therapeutically. Temporal Changes in PTEN and mTORC2 Regulation of Hematopoietic Stem Cell Self-Renewal and Leukemia SuppressionMagee et al.Cell Stem CellSeptember 07, 2012In BriefMyeloid leukemias driven by PTEN mutations are common in adults but rare in young children. Adult HSCs require PTEN to suppress the PI3-kinase pathway via TORC2 signaling whereas neonatal HSCs lack this tumor suppressor mechanism. Full-Text PDF Open ArchivemTOR Complex 1 Plays Critical Roles in Hematopoiesis and Pten-Loss-Evoked LeukemogenesisKalaitzidis et al.Cell Stem CellSeptember 07, 2012In BriefmTOR signaling is associated with hematopoietic function and leukemogenesis, but how unique mTOR complexes contribute to pathogenesis is poorly understood. Deletion of Raptor and Rictor, scaffolding proteins defining mTORC1 and mTORC2, reveal that PTEN-driven leukemia requires mTORC1, findings that suggest that chronic mTORC1 inhibition can cause deleterious responses. Full-Text PDF Open Archive
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