Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice

Kharas, Michael G.; Okabe, Rachel; Ganis, Jared J.; Gozo, Maricel; Khandan, Tulasi; Paktinat, Mahnaz; Gilliland, D. Gary; Gritsman, Kira

doi:10.1182/blood-2009-06-229443

Cited by 249 publications

(264 citation statements)

References 32 publications

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“…Considering the crucial role had by aberrantly activated Akt in the pathogenesis of T-ALL, 16,17 we studied the efficacy of MK-2206, a novel allosteric Akt inhibitor, 19 as a potential therapeutic agent. MK-2206 decreased the viability of T-ALL cell lines, in a concentration-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…14,15 Moreover, when a constitutively active, myristoylated allele of Akt was introduced into murine hematopoietic cells, mice developed a T-cell lymphoma with high frequency (65%). 16 Of note, the evolution of T-cell lymphoma to T-ALL was dependent, among other molecular alterations, also on Akt hyperactivation. 17 Hence, there is a strong rationale for developing novel, molecularly targeted therapies against Akt in T-ALL.…”

Section: Introductionmentioning

confidence: 99%

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Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

et al. 2012

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“…30 ROS production and metabolic rate are increased when HSCs transit from a quiescent state to a proliferation/differentiation state, a process that is mediated by the MTOR pathway. 30,31 Activation of AKT, an upstream regulator of MTOR, decreases autophagy in HSCs and promotes myeloid proliferation, 32 whereas deletion of Rptor/Raptor (regulatory-associated protein of MTOR, complex 1), encoding a component of MTORC1 (MTOR complex 1), enhances autophagy and decreases this myeloid cell population ( Table 1). 33 Moreover, HSC self-renewal can be restored by treatment with antioxidants or rapamycin.…”

Section: Role Of Autophagy In Hematopoietic Stem Cell Maintenancementioning

confidence: 99%

Autophagy-mediated regulation of macrophages and its applications for cancer

2013

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“…The mTOR pathway is frequently activated in blasts from patients with AML (36) and high-risk myelodysplastic syndrome (37). Furthermore, constitutive activation of the AKT/ mTOR pathway has been shown to induce acute leukemia in mice (38). Collectively, the results suggest that prolonged G-CSF treatment induces DNA damage in HSCs and genistein acts as a genoprotective agent in this setting.…”

Section: Discussionmentioning

confidence: 96%

Genistein Protects Hematopoietic Stem Cells against G-CSF–Induced DNA Damage

Souza

Silva

Calloway

et al. 2014

Cancer Prevention Research

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Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSFinduced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation. Cancer Prev Res; 7(5); 534-44. Ó2014 AACR.

show abstract

Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice

Cited by 249 publications

References 32 publications

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

Autophagy-mediated regulation of macrophages and its applications for cancer

Genistein Protects Hematopoietic Stem Cells against G-CSF–Induced DNA Damage

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