Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway

Marzec, Michał; Kasprzycka, Monika; Liu, X; El-Salem, Mouna; Halasa, Krzysztof; Raghunath, Puthiyaveettil N.; Bucki, Robert; Włodarski, Paweł; Wasik, Mariusz A.

doi:10.1038/sj.onc.1210346

Cited by 96 publications

(92 citation statements)

References 38 publications

(63 reference statements)

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“…Many primary systemic ALK-positive ALCLs express the NPM-ALK fusion protein, and this protein can elicit multiple signaling pathways, which are responsible for both cell transformation and maintenance of the neoplastic phenotype [19]. Of these signaling pathways, the Ras-extracellular signal-regulated kinase (ERK) pathway primarily takes charge of translating the downstream effectors, mTOR and its target proteins for ALCL proliferation [20][21][22]. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway also accounts for the small role for the ALCL proliferation [22].…”

Section: Discussionmentioning

confidence: 99%

18F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

Lee

Kim

et al. 2013

Nucl Med Mol Imaging

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Purpose Primary systemic anaplastic large cell lymphoma (ALCL) is divided into two entities according to the expression of anaplastic lymphoma kinase (ALK). We investigated 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) findings in primary systemic ALCL according to ALK expression. Methods Thirty-seven patients who had baseline PET before CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-based chemotherapy were enrolled. Among them, patients who underwent interim and/or post-therapy PET were further investigated for the treatment response and survival analysis. Baseline PET was analyzed visually and semiquantitatively using peakSUV, and interim and post-therapy PETs were visually analyzed. Results All cases were 18 F-FDG-avid on baseline PET. The peakSUV of ALK-positive ALCL (n =16, 18.7±10.5) was higher than that of ALK-negative ALCL (n =21, 10.0±4.9) (P =0.006). In ALK-negative ALCL, complete response (CR) rate in negative-interim PET was higher than positive-interim PET (100 % vs 37.5 %, P =0.02); however, there was no such difference in ALK-positive ALCL (100 % vs 75 %, P =0.19). The 3-year progression-free survival (PFS) was not significantly different between ALK-positive and ALK-negative ALCL (72.7 % vs 47.6 %, P =0.34). In ALK-negative ALCL, negative interim and post-therapy PET patients had better 3-year PFS than positive interim (83.3 % vs 25.0 %, P =0.06) and post-therapy PET patients (70.0 % vs 20.0 %, P =0.04). In contrast, ALK-positive ALCL had no such differences between PFS and PET results. Conclusions On baseline PET, all cases showed 18 F-FDGavidity, and ALK expression was related to higher 18 F-FDG uptake. ALK-positive patients tend to have better PFS than ALK-negative patients. Negative-interim PET was a good indicator of CR, and interim or post-therapy PET was helpful for predicting the prognosis only in the ALK-negative group.

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Section: Discussionmentioning

confidence: 99%

18F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

Lee

Kim

et al. 2013

Nucl Med Mol Imaging

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“…To achieve this goal, we first examined an IL-3-dependent lymphoid BaF3 cell line stably transfected with a vector containing either the native NPM/ALK gene or the K210R NPM/ALK mutant devoid of enzymatic activity (Zhang et al, 2002;Marzec et al, 2007). Only BaF3 cells carrying the intact NPM/ALK gene strongly expressed HIF1a regardless of the presence or absence of IL-3 (Figure 2a).…”

Section: Expression Of Hif1a Is Induced By Npm/alkmentioning

confidence: 99%

“…Similarly, they showed a relatively increased proliferation rate as determined by the bromodeoxyuridine uptake ( Figure 4b). As the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has a key role in the proliferation of ALK þ TCL cells (Marzec et al, 2007), we next examined the impact of HIF1a depletion on mTORC1 signaling (Figure 4c). In accordance with the cell proliferation data (Figure 4b), HIF1a loss enhanced Figure 3 NPM/ALK induces HIF1a expression through STAT3.…”

Section: Role Of Hif1a In Alk þ Tcl Cell Growth Proliferation and Vementioning

confidence: 99%

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

et al. 2010

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“…Although conventional chemotherapy induces a high rate of complete remission, relapse is frequently observed, and these patients eventually present poor clinical outcome. 1,2 Insights into the pathogenesis of T-cell malignancies have recently emerged, including alternations in cell proliferation and apoptosis, and the dysregulations of multiple intracellular signaling pathways, such as nuclear factor (NF)-kB, 3,4 extracellular signal-regulating kinase 1/2 (ERK1/2), 5,6 AKT, 5,7 c-jun N-terminal kinase (JNK) 8 and p38 mitogenactivated protein kinase (p38MAPK). 9 Therefore, new regimens need to be investigated, particularly those non-chemotherapeutic agents that specifically target pathways on which malignant T cells depend for their survival.…”

Section: Introductionmentioning

confidence: 99%

The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis

Wang

et al. 2009

Leukemia

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Interactions between inhibitors of the proteasome and histone deacetylases have been examined in human T-leukemia/ lymphoma cells both in vitro and in vivo. Co-exposure of cells to bortezomib and suberoylanilide hydroxamic acid (SAHA) synergistically induces T-leukemia/lymphoma cells to undergo apoptosis, consistent with a significant increase in mitochondrial injury and caspase activation. These events are accompanied by inhibition of cyto-protective signaling pathways, including the nuclear factor (NF)-jB, Raf-1/mitogen-induced extracellular kinase (MEK)/extracellular signal-related kinase (ERK) and AKT pathways, and activation of stress-related cascades, including the stress-activated kinases c-jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK). Moreover, bortezomib in conjunction with SAHA efficiently induces apoptosis of primary T-leukemia/lymphoma cells and inhibits tumor growth in a murine xenograft model established with subcutaneous injection of Jurkat cells. Taken together, these findings confirm the synergistic anti-tumor effect of the proteasome and histone deacetylase inhibitors, and provide an insight into the future clinical applications of bortezomib-SAHA combining regimen in treating T-cell malignancies.

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Oncogenic tyrosine kinase NPM/ALK induces activation of the rapamycin-sensitive mTOR signaling pathway

Cited by 96 publications

References 38 publications

18F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

18F-FDG PET in Patients with Primary Systemic Anaplastic Large Cell Lymphoma: Differential Features According to Expression of Anaplastic Lymphoma Kinase

Oncogenic kinase NPM/ALK induces expression of HIF1α mRNA

The proteasome inhibitor bortezomib interacts synergistically with the histone deacetylase inhibitor suberoylanilide hydroxamic acid to induce T-leukemia/lymphoma cells apoptosis

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