G2/M checkpoint stringency is a key parameter in the sensitivity of AML cells to genotoxic stress

Didier, Christine; Cavelier, Cindy; Quaranta, Muriel; Mo, Galcera; Demur, Cécile; Laurent, Guy; Manenti, Stéphane; Ducommun, Bernard

doi:10.1038/sj.onc.1211041

Cited by 34 publications

(37 citation statements)

References 39 publications

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“…One hypothesis could be the existence of still undefined function(s) of Plk1 during the G 1 phase of the cell cycle. Interestingly, we observed that in the KG1 leukemic cell line, concentrations of Plk1 inhibitor that completely inhibit cell proliferation did not induce a complete block in G 2 /M, as can be induced with DNA damaging agents like VP-16 for instance, 41 but rather a mixture of G 1 and G 2 /M cell populations (Fig. 4).…”

Section: Hypothesis To Explain the Functional Relationship Between Plmentioning

confidence: 89%

A functional link between Polo-like kinase 1 and the mammalian Target-Of-Rapamycin pathway?

Renner

Créancier²,

Santos³

et al. 2010

Cell Cycle

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Polo like kinase-1 is a key effector of cell division and its overexpression in several cancers is often linked with negative prognostic. We recently described that Plk1 is overexpressed in acute myeloid leukemia, and that its inhibition selectively reduces the proliferation of leukemic cells. Here, we report that Plk1 inhibition or depletion using pharmacological and siRNA approaches decreased the phosphorylation of two mTOR substrates in AML cells. In HCT116 cells, inducible expression of a constitutively active form of Plk1 leads to activation of mTOR, as shown by increased phosphorylation of its 4E-BP1 and RPS6 down-stream targets. In addition, cells overexpressing the active form of Plk1 were characterized by abnormal growth that could be reversed by rapamycin, a specific inhibitor of the TORC1 complex. Altogether these data suggest the existence of a molecular and functional link between the Plk1 mitotic kinase and the mTOR pathway. Given the different established functions of Plk1 and mTOR during the cell cycle, we will discuss the possible meaning of this functional relationship.

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Section: Hypothesis To Explain the Functional Relationship Between Plmentioning

confidence: 89%

A functional link between Polo-like kinase 1 and the mammalian Target-Of-Rapamycin pathway?

Renner

Créancier²,

Santos³

et al. 2010

Cell Cycle

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“…These data are shown in Fig. 4A, together with the phospho-H2AX levels and the sensitization factor (SF), which is a ratio between the IC 50 for ara-C alone and in combination with UCN-01 (31). They confirm that, as observed in a clinical setting, complex karyotype samples are more resistant to ara-C treatment than normal ones (mean IC 50 , 9.8 nmol/L ± 0.6; n = 5 versus 5.9 nmol/L ± 0.4; n = 4; *, P = 0.05).…”

Section: Resultsmentioning

confidence: 99%

Constitutive Activation of the DNA Damage Signaling Pathway in Acute Myeloid Leukemia with Complex Karyotype: Potential Importance for Checkpoint Targeting Therapy

et al. 2009

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Genomic instability in solid tumors participates in the oncogenetic process and is associated with the activation of the DNA damage response pathway. Here, we report the activation of the constitutive DNA damage and checkpoint pathway associated with complex karyotypes in samples from patients with acute myeloid leukemia (AML). We show that antagonizing CHK1 kinase with a small inhibitory compound or by RNA interference strongly reduces the clonogenic properties of high-DNA damage level AML samples, particularly those with complex karyotypes. Moreover, we observe a beneficial effect of CHK1 inhibition in high-DNA damage level AML samples treated with 1-β-D-arabinofuranosylcytosine. In contrast, CHK1 inhibition has no effect on the clonogenic properties of normal hematopoietic progenitors. All together, our results indicate that CHK1 inhibition may represent an attractive therapeutic opportunity in AML with complex karyotype.

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“…At the G1/S checkpoint, DNA synthesis is inhibited, whereas intra-S phase arrest blocks mitotic entry until the S-phase is completed [30]. Finally, at the G2/M checkpoint, damaged cells are arrested in order to allow for cell repair or apoptosis [49]. CDC25s are inactivated by checkpoint kinases (CHK1 and CHK2) in an ataxia-telangiectasia mutated (ATM) and AT and Rad3-related (ATR) kinases-dependent manner.…”

Section: Cell Cycle Arrest and Cdc25 Inhibitionmentioning

confidence: 99%

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

et al. 2014

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Abstract:The cell division cycle 25 (CDC25) phosphatases include CDC25A, CDC25B and CDC25C. These three molecules are important regulators of several steps in the cell cycle, including the activation of various cyclin-dependent kinases (CDKs). CDC25s seem to have a role in the development of several human malignancies, including acute myeloid leukemia (AML); and CDC25 inhibition is therefore considered as a possible anticancer strategy. Firstly, upregulation of CDC25A can enhance cell proliferation and the expression seems to be controlled through PI3K-Akt-mTOR signaling, a pathway possibly mediating chemoresistance in human AML. Loss of CDC25A is also important for the cell cycle arrest caused by differentiation induction of malignant hematopoietic cells. Secondly, high CDC25B expression is associated with resistance against the antiproliferative effect of PI3K-Akt-mTOR inhibitors in primary human AML cells, and inhibition of this isoform seems to reduce AML cell line proliferation through effects on NFκB and p300. Finally, CDC25C seems important for the phenotype of AML cells at least for a subset of patients. Many of the identified CDC25 inhibitors show cross-reactivity among the three CDC25 isoforms. Thus, by using such cross-reactive inhibitors it may become possible to inhibit OPEN ACCESSMolecules 2014, 19 18415 several molecular events in the regulation of cell cycle progression and even cytoplasmic signaling, including activation of several CDKs, through the use of a single drug. Such combined strategies will probably be an advantage in human cancer treatment.

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G2/M checkpoint stringency is a key parameter in the sensitivity of AML cells to genotoxic stress

Cited by 34 publications

References 39 publications

A functional link between Polo-like kinase 1 and the mammalian Target-Of-Rapamycin pathway?

A functional link between Polo-like kinase 1 and the mammalian Target-Of-Rapamycin pathway?

Constitutive Activation of the DNA Damage Signaling Pathway in Acute Myeloid Leukemia with Complex Karyotype: Potential Importance for Checkpoint Targeting Therapy

Therapeutic Targeting the Cell Division Cycle 25 (CDC25) Phosphatases in Human Acute Myeloid Leukemia — The Possibility to Target Several Kinases through Inhibition of the Various CDC25 Isoforms

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