Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes

Boi, Michela; Todaro, Maria Chiara; Vurchio, Valentina; Yang, Shao Ning; Moon, John H.; Kwee, Ivo; Rinaldi, Andrea; Pan, Heng; Crescenzo, Ramona; Cheng, Mangeng; Cerchietti, Leandro; Elemento, Olivier; Riveiro, María E.; Cvitkovic, Esteban; Bertoni, Francesco; Inghirami, Giorgio

doi:10.18632/oncotarget.12876

Cited by 21 publications

(10 citation statements)

References 50 publications

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“…Thus far, only an isocorydine derivative (d-ICD) or BETis have been demonstrated to hamper the expression of IGF2BP3 (19,39,49). Here, we provide evidence that the BETi JQ1, which has marked antitumor activity against several hematologic malignancies as well as solid tumors including Ewing sarcoma (41,53,54), decreases the expression of IGF2BP3 and some of its targets (ABCF1, ABCG2, CD44, MMP9) and suppressed the capacity of growth of Ewing sarcoma cells under anchorage-independent conditions. BET proteins are major epigenetic players, connecting chromatin structures with gene expression changes.…”

Section: Discussionmentioning

confidence: 82%

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

Mancarella

Pasello

Ventura

et al. 2018

Clinical Cancer Research

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Large-scale sequencing studies have indicated that besides genomic alterations, the posttranscriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma. We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of Ewing sarcoma aggressiveness. Explorative study was performed in 14 patients with localized Ewing sarcoma using RNA sequencing. Next, 128 patients with localized Ewing sarcoma were divided into two cohorts. In the training set, 29 Ewing sarcoma samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 Ewing sarcoma samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.Univariate and multivariate analyses indicated as a potent indicator of poor prognosis. Furthermore, mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of and could identify different patient outcomes-high and low levels indicated poor survival (25%), whereas low and high levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of Ewing sarcoma cells to grow under anchorage-independent conditions. The combined assessment of and predicts recurrence in Ewing sarcoma patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated. .

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Section: Discussionmentioning

confidence: 82%

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

Mancarella

Pasello

Ventura

et al. 2018

Clinical Cancer Research

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“…Numerous studies have shown that c-MYC is essential for multiple myeloma cell survival and that IRF4 regulates its expression [ 37 ]. Moreover, it has been recently demonstrated that IRF4 and MYC signaling play an essential role ALCL cell lines survival [ 38 ] and that the treatment with BET family inhibitors may have a therapeutic efficacy in ALK positive ALCL [ 39 ]. Therefore, we tested whether the combination of pomalidomide with the BET family inhibitor JQ1, which inhibits MYC and IRF4 expression, could sensitize ALCL cells to IMiDs treatment.…”

Section: Resultsmentioning

confidence: 99%

“…It has been recently demonstrated that IRF4 and MYC signaling play an essential role ALCL cell lines survival [ 38 , 39 ]. Interestingly, the possibility of combinatorial block of MYC and IRF4 gene expression was greatly advanced by the demonstration that treatment of multiple myeloma tumor cells with the BET-bromodomain inhibitor JQ1 led to loss of BRD4 at super-enhancers, and consequent transcription elongation defects of genes with super-enhancers, including MYC and IFR4 [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Bandini

Pupuleku

Spaccarotella

et al. 2018

Cancers

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Systemic anaplastic large cell lymphomas (ALCL) are a category of T-cell non-Hodgkin’s lymphomas which can be divided into anaplastic lymphoma kinase (ALK) positive and ALK negative subgroups, based on ALK gene rearrangements. Among several pathways aberrantly activated in ALCL, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) is shared by all ALK positive ALCL and has been detected in a subgroup of ALK negative ALCL. To discover essential mediators of STAT3 oncogenic activity that may represent feasible targets for ALCL therapies, we combined gene expression profiling analysis and RNA interference functional approaches. A shRNA screening of STAT3-modulated genes identified interferon regulatory factor 4 (IRF4) as a key driver of ALCL cell survival. Accordingly, ectopic IRF4 expression partially rescued STAT3 knock-down effects. Treatment with immunomodulatory drugs (IMiDs) induced IRF4 down regulation and resulted in cell death, a phenotype rescued by IRF4 overexpression. However, the majority of ALCL cell lines were poorly responsive to IMiDs treatment. Combination with JQ1, a bromodomain and extra-terminal (BET) family antagonist known to inhibit MYC and IRF4, increased sensitivity to IMiDs. Overall, these results show that IRF4 is involved in STAT3-oncogenic signaling and its inhibition provides alternative avenues for the design of novel/combination therapies of ALCL.

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“…Bromodomain and extraterminal domain (BET) inhibitors represent a promising group of therapeutics that inhibit YAP/p21/MYC signaling, MYC and IRF4 expression, and the E2F and mTORC pathways. [46][47][48] Because MYC, E2F, and mTORC represented the top gene sets associated with MSC E116K overexpression by GSEA, we in Karpas 299 cells, followed by mass spectrometry, revealed similar musculin:E-protein interactions. There was a slightly increased interaction between MSC E116K and E2A isoforms, although none of the differences was statistically significant.…”

Section: Potential Therapeutic Targeting Of Alcls With Msc E116kmentioning

confidence: 94%

Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma

Luchtel¹,

Zimmermann

Hu³

et al. 2019

Blood

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Anaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK−, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK− ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK− ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin–bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation–sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30–IRF4–MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30–IRF4–MYC axis and cell cycle progression in a unique subset of ALCLs.

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Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes

Cited by 21 publications

References 50 publications

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post-Transcriptional Regulator of Ewing Sarcoma Malignancy

IRF4 Mediates the Oncogenic Effects of STAT3 in Anaplastic Large Cell Lymphomas

Recurrent MSCE116K mutations in ALK-negative anaplastic large cell lymphoma

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