Upregulation of the CDC25A phosphatase downstream of the NPM/ALK oncogene participates in anaplastic large cell lymphoma enhanced proliferation

Fernandez-Vidal, Anne; Mazars, Anne; Gautier, Emilie-Fleur; Prevost, Grégoire; Payrastre, Bernard; Manenti, Stéphane

doi:10.4161/cc.8.9.8302

Cited by 19 publications

(25 citation statements)

References 22 publications

(31 reference statements)

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“…Findings analogous to our own have been found in other systems; for example, cdc25A depletion after cytarabine treatment was found to be dependent on another component of the pathway (rad9), such that rad9 -/-mouse embryonic stem cells show increased sensitivity to cytarabine (38). While this article was being prepared, an article was published indicating that NPM/ALK and BCR/ABL as well as FLT3-ITD are associated with constitutive expression of cdc25A (37). Our study thus may provide a paradigm for exploring the effect of other activating mutations on the S-phase checkpoint response to a range of S-phase drugs.…”

Section: Discussionmentioning

confidence: 73%

“…However, this might not be the relevant pathway: it is also of note that Pim-1, another major transcriptional target of FLT3-ITDs (34), is reported to activate cdc25A (35), although the mechanism is unclear (36). Recently, a phosphoinositide 3-kinase inhibitor has been used to downregulate cdc25A expression in Ba/F3 cells expressing a FLT3-ITD (37). Thus, there may be more than one pathway by which FLT3-ITDs upregulate cdc25A expression.…”

Section: Discussionmentioning

confidence: 99%

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Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

Seedhouse

Grundy²,

Shang³

et al. 2009

Clinical Cancer Research

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Purpose: Acute myeloid leukemia cells with an internal tandem duplication mutation of FLT3 (FLT3-ITD) have effective DNA repair mechanisms on exposure to drugs. Despite this, the phenotype is not associated with primary resistant disease. We show defects in the response of mutant FLT3 AML cells to the S-phase drug clofarabine that could account for the apparent contradiction. Experimental Design: We studied responses of AML cells to clofarabine in vitro. Results: When treated with a short pulse of clofarabine, FLT3-ITD-harboring MOLM-13 and MV4.11 cells undergo similar damage levels (γH2AX foci) to wild-type cells but have a better repair capability than wild-type cells. However, whereas the wild-type cells undergo rapid S-phase arrest, the S-phase checkpoint fails in mutant cells. Cell cycle arrest in response to DNA damage in S phase is effected via loss of the transcriptional regulator cdc25A. This loss is reduced or absent in clofarabine-treated FLT3 mutant cells. Furthermore, cdc25A message levels are maintained by the FLT3-ITD, such that message is reduced by 87.5% on exposure to FLT3 small interfering RNA. Primary FLT3-ITD samples from untreated patients also display impaired cell cycle arrest and show enhanced sensitivity on prolonged treatment with clofarabine compared with wild-type samples. Clofarabine is a second-generation purine nucleoside analogue with favorable pharmacologic properties (resistance to deaminase degradation and stability in gastric acid) and is in increasing clinical use for the treatment of AML (5-9). Because of the potential oral availability and its acceptable toxicity with respect to mucositis and alopecia, its use has recently been explored in older AML patients with promising results. 3Mechanisms supporting heterogeneity in sensitivity and resistance to clofarabine have been reported in the literature; particularly, a variability in the cellular accumulation of clofarabine triphosphate in circulating blasts has been recorded (6, 7). We have previously shown efficient DNA repair following anthracycline exposure in AML cells with a FLT3-ITD (10) and were thus initially interested to discover whether DNA damage and repair mechanisms are important in the response of FLT3-ITD cells to clofarabine. There is a well-characterized assay (the measurement of γH2AX) that can be used as a biomarker of the effectiveness of clofarabine at reaching its DNA target and inducing a damage response (7,11). The use of this assay has enabled us to focus on events subsequent to clofarabine-induced DNA damage and to dissect mechanisms by which cells proceed to apoptosis or recovery subsequent to the initial damage response signals.The damage response pathway is closely linked to cell cycle arrest mechanisms. In a well-documented but fast-evolving model of cell cycle arrest in S phase (the phase in which 3 A.K. Burnett et al

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

Seedhouse

Grundy²,

Shang³

et al. 2009

Clinical Cancer Research

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“…Signal transduction inhibitors which target the PI3K/PTEN/Akt/mTOR and Raf/MEK/ERK pathways may prove to enhance chemotherapy. 6,22,30,33,35,36,[38][39][40][41][42][43][44][45][46] Furthermore targeting of the bone marrow microenvironment and the cancer stem cells with combinations of these signal transduction inhibitors and chemotherapy may enhance cancer treatment. [32][33][34][35][36]47 There are also complicated interactions between p53 and PI3K/PTEN/Akt/mTOR, Raf/MEK/ ERK and other signaling and apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

et al. 2010

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“…126 Recent evidence points to a role of the PI3K/AKT pathway to cause constitutive activation of the dual specificity phosphatase CDC25A, leading to enhanced proliferation. 127 Also, a positive synergistic effect between the sonic hedgehog (SHH)/GLI1 and PI3K/AKT pathways has been described that contributes to the lymphomagenic effect of NPM1-ALK. 128 The activated phosphorylated form of the STAT3 transcription factor that has been detected in 84% of ALK + ALCL tumour samples, as well as in cell lines and in thymocytes and tumour tissues of NPM1-ALK transgenic mice 98,[129][130][131][132][133] leads to the enhanced expression of antiapoptotic proteins, cell-cycle regulators and immunosuppressive proteins such as BCL-XL , survivin, cyclin D3, C/EBPb, myeloid leukaemia sequence 1 (MCL1) and PD-L1 (CD274).…”

Section: Regulation Of Apoptosismentioning

confidence: 99%

Oncogenic Anaplastic Lymphoma Kinase Rearrangements in Lymphoma

Roosbroeck¹,

Włodarska²

2009

European Oncology &Amp; Haematology

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Lymphomas expressing anaplastic lymphoma kinase (ALK) represent two distinct lymphoma entities: ALK-positive T-/null-cell anaplastic large cell lymphoma (ALK + ALCL) and ALK-positive large B-cell lymphoma (ALK + LBCL). In both subtypes, the inappropriate expression of ALK is driven by 2p23/ALK-involving chromosomal translocations found to target several partner genes. These translocations lead to constitutively activated and oncogenic ALK fusions, of which nucleophosmin (NPM1)-ALK associated with t(2;5)(p23;q35) is the most common. Recently, various ALK fusions, including those previously described in lymphomas, have been identified in several types of nonhaematological malignancy. Identification of further types of ALK + tumours is clinically important because in future these patients may benefit from targeted therapy, already applied in neoplasms driven by, for example, the mutated ABL1, KIT and PDGFRA/B tyrosine kinases.In this article, we will focus mainly on oncogenic ALK rearrangements in lymphomas and their molecular consequences. KeywordsOncogene, anaplastic lymphoma kinase, anaplastic large cell lymphoma, large B-cell lymphoma The inappropriate expression of ALK in ALK + ALCL derives from chromosomal translocations targeting the 2p23/ALK locus. Occurring in 84% of ALK + ALCL, the most frequent, t(2;5)(p23;q35), results in the fusion of the amino-terminal end of NPM (currently designated as NPM1) with the intracytoplasmic portion of ALK.

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Upregulation of the CDC25A phosphatase downstream of the NPM/ALK oncogene participates in anaplastic large cell lymphoma enhanced proliferation

Cited by 19 publications

References 22 publications

Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

Impaired S-Phase Arrest in Acute Myeloid Leukemia Cells with a FLT3 Internal Tandem Duplication Treated with Clofarabine

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy

Oncogenic Anaplastic Lymphoma Kinase Rearrangements in Lymphoma

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