Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable

Min, Yoo Hong; Eom, Ju In; Cheong, June Won; Maeng, Hoyoung; Kim, J. Y.; Jeung, Hoi Kyung; Lee, S. T.; Lee, M. H.; Hahn, Jae Won; Ko, Yun Woong

doi:10.1038/sj.leu.2402874

Cited by 219 publications

(184 citation statements)

References 7 publications

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“…In contrast, the non-a isoforms of class I PI3K, p110b, p110g and p110d, have an inherent oncogenic activity as wild-type proteins. This observation is in accord with evidence showing that p110d and p110g are involved in the development and progression of malignancies, such as acute and chronic myeloid leukemia (Skorski et al, 1995(Skorski et al, , 1997Klejman et al, 2002;Min et al, 2003;Kharas et al, 2004;Kubota et al, 2004;Grandage et al, 2005;Sujobert et al, 2005;Hickey and Cotter, 2006;Martelli et al, 2006;Billottet et al). Recent structural studies have advanced our understanding of the mechanisms that mediate the gain of function in cancer-specific mutations of p110a (Miled et al, 2007).…”

Section: Discussionsupporting

confidence: 85%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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Section: Discussionsupporting

confidence: 85%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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“…As described earlier, normal CD34 þ cells from healthy donors displayed a low level of phospho-Akt (data not shown). 5,8 To analyse the characteristics of the AML patients according to the level of phospho-Akt, patients were stratified according to their median rMFI ( ± 2.3 for Thr308 and ± 1.3 for Ser473). Patients with an rMFI value 42.3 or 41.3 were referred to as Thr308 high or Ser473 high , respectively, whereas the others were referred as Thr308 low or Ser473 low .…”

Section: Correlation Between Akt Thr 308 and Cytogenetic Risk In Aml mentioning

confidence: 99%

“…In a retrospective study, constitutive phospho-Akt on Ser473 seemed to be an adverse prognostic factor for survival. 5 Recently, the simultaneous activation of PKCa, ERK2, pERK2 and phospho-Akt pathways was shown to predict poor outcome in a large series of AML patients. 6 In this study, although phospho-Akt was an adverse prognostic factor per se, the site of phospho-Akt determined by western blotting was not indicated.…”

Section: Introductionmentioning

confidence: 99%

The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia

et al. 2009

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The phosphoinositide 3-kinase/Akt pathway is an important signalling pathway governing cell survival and proliferation in acute myeloid leukaemia (AML). As full activation of Akt requires phosphorylation on both threonine 308 (Thr308) and serine 473 (Ser473) residues, we studied the level of phosphorylation on the both sites in 58 AML samples by flow cytometry. The ratio of the mean fluorescence intensity of Thr308 and Ser473 represented a continuum ranging from 0.3 to 5.6 and from 0.4 to 2.87, respectively. There were no significant correlations between age, gender, French-American-British classification, leukocytosis, FLT3-ITD and Akt phosphorylation. However, the level of phosphorylation on Thr308, but not on Ser473, was significantly correlated with high-risk karyotype. Thr308 high patients had significantly shorter overall survival (11 vs 47 months; P ¼ 0.01), event-free survival (9 vs 26 months; P ¼ 0.005) and relapse-free survival (10 months vs not reached; P ¼ 0.02) than Thr308 low patients. Neither screening for AKT1 E17K mutation nor changes in the level of PTEN expression and phosphorylation could be linked to increased phosphorylation on Thr308 in high-risk cytogenetic AML cells. However, PP2A activity was significantly reduced in high-risk samples compared with intermediate-risk samples. Moreover, the specific Akt inhibitor, Akti-1/2, inhibited cell proliferation and clonogenic properties, and induced apoptosis in AML cells with high-risk cytogenetics, suggesting that Akt may represent a therapeutic target in high-risk AML.

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“…[3][4][5] Studies have shown that the PI3K/Akt/mTOR pathway is constitutively activated in 50-70% of acute myeloid leukemia (AML) cases, suggesting that this pathway could constitute a therapeutic target. [6][7][8][9][10][11] p53 is the most frequently inactivated protein in human cancer, and more than 50% of all solid tumors carry p53 mutations in the TP53 gene that abrogate its DNA binding and transactivation activity. 12 Although TP53 mutations rarely occur in AML, it has been suggested that inactivation of wild-type p53 frequently occurs through binding to its principal cellular regulator murine double minute 2 homologue (Mdm2).…”

Section: Introductionmentioning

confidence: 99%

The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML

et al. 2008

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Activation of the phosphatidylinositol-3 kinase/Akt/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and inactivation of wild-type p53 by murine double minute 2 homologue (Mdm2) overexpression are frequent molecular events in acute myeloid leukemia (AML). We investigated the interaction of PI3K/Akt/mTOR and p53 pathways after their simultaneous blockade using the dual PI3K/mTOR inhibitor PI-103 and the Mdm2 inhibitor Nutlin-3. We found that PI-103, which itself has modest apoptogenic activity, acts synergistically with Nutlin-3 to induce apoptosis in a wild-type p53-dependent fashion. PI-103 synergized with Nutlin-3 to induce Bax conformational change and caspase-3 activation, despite its inhibitory effect on p53 induction. The PI-103/Nutlin-3 combination caused profound dephosphorylation of 4E-BP1 and decreased expression of many proteins including Mdm2, p21, Noxa, Bcl-2 and survivin, which can affect mitochondrial stability. We suggest that PI-103 actively enhances downstream p53 signaling and that a combination strategy aimed at inhibiting PI3K/Akt/mTOR signaling and activating p53 signaling is potentially effective in AML, where TP53 mutations are rare and downstream p53 signaling is intact.

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Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable

Abstract: fusion by insertion of 21q into 12p has been previously described, 6 we are the first to report the opposite phenomenon, namely insertion of 12p into 21q, producing the same result.

Cited by 219 publications

References 7 publications

Oncogenic signaling of class I PI3K isoforms

Oncogenic signaling of class I PI3K isoforms

The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia

The dual PI3 kinase/mTOR inhibitor PI-103 prevents p53 induction by Mdm2 inhibition but enhances p53-mediated mitochondrial apoptosis in p53 wild-type AML

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