Mutation analysis of PTEN/MMAC1 in acute myeloid leukemia

Liu, Ta-Chih; Lin, Pei; Chang, Jan‐Gowth; Lee, Jing-Ping; Chen, Tyen-Po; Lin, Sheng-Fung

doi:10.1002/(sici)1096-8652(200004)63:4<170::aid-ajh2>3.0.co;2-0

Cited by 76 publications

(58 citation statements)

References 23 publications

(35 reference statements)

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“…20 Although neither inactivating mutations nor loss of heterozygosity have been shown in AML, the level of protein expression varies between studies but has never been correlated with cytogenetic sub-classes of AML. 4,21 PTEN phosphorylation at the C-terminal regulatory domain is known to induce a decrease in PTEN activity towards its lipid substrates. 22,23 It has been shown that PTEN phosphorylation on Ser380/Thr382/Thr383 AKT phosphorylation in AML N Gallay et al residues is associated with an increase in phospho-Akt and poor OS in AML.…”

Section: Absence Of Akt Mutation In Aml With High-risk Cytogeneticsmentioning

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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Section: Absence Of Akt Mutation In Aml With High-risk Cytogeneticsmentioning

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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“…Moreover, no loss of heterozygosity (LOH) or other types of genetic mutations were observed. 260 PTEN-inactivating mutations do not appear to occur very frequently in AML. 261,262 Therefore, the importance, if any, of PTEN in causing Akt activation in AML blast cells remains unclear.…”

Section: Roles Of the Pi3k/pten/akt/mtor Pathway In Leukemiamentioning

confidence: 99%

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

et al. 2008

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Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia

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“…We examined the level and localization of p-T451 PKR in the PTEN-positive HL60 27,28 and PTEN-negative CCRF-CEM (CEM) cell lines 29 , from cytoplasmic and nuclear lysates of untreated CEM cells or immunoprecipitations from the nuclear lysate using a-N-ter hPKR (antigen: aa1-101 of hPKR), a-PKR (D20) (antigen: aa458-508 of mPKR), a-hPKR (K17) (antigen: C-terminus of hPKR), a-C-ter hPKR (antigen: aa502-551 of hPKR) and a-p-T451 PKR, was separated by 10% SDS-polyacrylamide gel electrophoresis, transferred and immunoblotted with the indicated antibody. The data are representative of at least three independent experiments.…”

Section: Acute Leukemia Cell Lines Contain Diverse Forms Of Pkrmentioning

confidence: 99%

Multiple forms of PKR present in the nuclei of acute leukemia cells represent an active kinase that is responsive to stress

et al. 2010

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A number of cancers possess constitutive activity of the dsRNA-dependent kinase, PKR. Inhibition of PKR in these cancers leads to tumor cell death. We recently reported the increased presence of PKR phosphorylated on Thr451 (p-T451 PKR) in clinical samples from myelodysplastic syndrome (MDS) patients and acute leukemia cell lines. Whereas p-T451 PKR in low-risk patient samples or PTEN-positive acute leukemia cell lines was mostly cytoplasmic, in high-risk patient samples and acute leukemia cell lines deficient in PTEN, p-T451 PKR was mainly nuclear. As nuclear activity of PKR has not been previously characterized, we examined the status of nuclear PKR in acute leukemia cell lines. Using antibodies to N-terminus, C-terminus and the kinase domain in conjunction with a proteomics approach, we found that PKR exists in diverse molecular weight forms in the nucleus. Analysis of PKR transcripts by reverse transcriptase-PCR, and PKR-derived peptides by MS/MS revealed that these forms were the result of post-translational modifications (PTMs). Biochemical analysis demonstrated that nuclear PKR is an active kinase that can respond to stress. Given the association of PKR with PTEN and the Fanconi complex, these results indicate that PKR likely has other previously unrecognized roles in nuclear signaling that may contribute to leukemic development.

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Mutation analysis of PTEN/MMAC1 in acute myeloid leukemia

Cited by 76 publications

References 23 publications

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 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

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

Multiple forms of PKR present in the nuclei of acute leukemia cells represent an active kinase that is responsive to stress

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