Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes

Piva, Roberto; Pellegrino, Elisa; Mattioli, Michela; Agnelli, Luca; Lombardi, Luigia; Boccalatte, Francesco; Costa, Giulia; Ruggeri, Bruce; Cheng, Mangeng; Chiarle, Roberto; Palestro, Giorgio; Neri, Antonino; Inghirami, Giorgio

doi:10.1172/jci29401

Cited by 142 publications

(140 citation statements)

References 49 publications

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“…Its aberrant expression has been implicated in the pathogenesis of several epithelial tumors (7)(8)(9) and more recently, in NPM-ALK lymphoid transformation (5,10,11). In ALK þ ALCLs, C/EBPb expression depends on the tyrosine kinase activity of NPM-ALK and is transcriptionnally induced through the STAT3 signaling pathway, although no STAT3-specific binding sites have been observed in the C/EBP promoter region (5,10,11). On the other hand, C/EBPb, has been intensely studied for its critical role in adipocyte differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…The dependence of C/EBPb gene transcription on the STAT3 signaling pathway in ALK þ ALCLs has recently been shown in 3 independent studies (5,10,11), consistent with the notion that the C/EBPb promoter is targeted by several transcription factors, including CREB/ATF and Sp1 proteins, C/EBP family members, and STAT3, albeit indirectly, in response to a variety of stimuli (12). However, C/EBPb mRNA also possesses a 3 0 -untranslated region (3 0 -UTR) that contains U-and AU-rich elements (ARE), that has been shown to bind the AU-binding protein (AUBP) HuR in adipocytes (13).…”

Section: Introductionmentioning

confidence: 96%

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HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

Bergalet

Fawal

Lopez

et al. 2011

Molecular Cancer Research

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The CCAAT/enhancer-binding protein b (C/EBPb) plays a major role in the pathogenesis of anaplastic large cell lymphomas (ALCL) that express the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) tyrosine kinase (ALK þ ). Although ALK-mediated C/EBPb transcriptional activation has been reported, C/EBPb mRNA possesses U-and AU-rich domains in its 3 0 -untranslated region (3 0 -UTR) that might be privileged targets for posttranscriptional control in ALK þ ALCLs. The purpose of this study was to explore this possibility. By using human ALCL-derived cells and a murine model of ALK-transformed cells, we show that the AU-binding protein HuR binds to the 3 0

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

Bergalet

Fawal

Lopez

et al. 2011

Molecular Cancer Research

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“…Bfl-1 was observed to be essential for the survival of malignant B-cells 385 . It has also been seen to be overexpressed in acute lymphoblastic and chronic lymphocytic leukemia (CLL) 386 , mantle cell lymphoma 386 , and large B-cell lymphoma 387 . Indeed, high Bfl-1 expression was seen to correlate with the more severe cases of CLL 373 .…”

Section: The Role Of Bfl-1 In Cancermentioning

confidence: 99%

“…As such, although overexpression of Bfl-1 alone was not tumorigenic in mice 391 , Bfl-1 overexpression led to increased E1A-induced transformation 392 , and enhanced mycinduced leukemogenesis 393 . It has also been suggested that Bfl-1 contributes to the transformation of pre-T-cells when T-cell receptor signalling is deregulated 394 and that, along with CEBP, Bfl-1 is essential for anaplastic lymphoma kinase (ALK)-driven transformation to anaplastic large cell lymphoma 387 .…”

Section: The Role Of Bfl-1 In Cancermentioning

confidence: 99%

“…For example, Bfl-1, with CEBP, was shown to be essential for the transformation to anaplastic large cell lymphoma 387 , and the overexpression of Bfl-1 in mice sensitized the animals to transformations caused by oncogenes such as E1A and myc 392,393 , so it is feasible that Bfl-1 could have a tumourigenic role in melanoma development, possibly in combination with the BRaf mutation, or PTEN deletion.…”

Section: : Concluding Remarksmentioning

confidence: 99%

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Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Molecular Classification of the Peripheral T‐cell Lymphomas

Herek

Iqbal

2021

The Peripheral T‐Cell Lymphomas

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Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and Bcl2A1 as critical target genes

Cited by 142 publications

References 49 publications

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

HuR-Mediated Control of C/EBPβ mRNA Stability and Translation in ALK-Positive Anaplastic Large Cell Lymphomas

Role of the pro-survival molecule Bfl-1 in melanoma

Molecular Classification of the Peripheral T‐cell Lymphomas

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