miR-939 acts as tumor suppressor by modulating JUNB transcriptional activity in pediatric anaplastic large cell lymphoma

Garbin, Anna; Lovisa, Federica; Holmes, Antony B.; Damanti, Carlotta C.; Gallingani, Ilaria; Carraro, Elisa; Accordi, Benedetta; Veltri, Giulia; Marco, Pizzi; d'Amore, Emanuele S G; Pillon, Marta; Biffi, Alessandra; Basso, Katia; Mussolin, Lara

doi:10.3324/haematol.2019.241307

Cited by 10 publications

(9 citation statements)

References 13 publications

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“…Under normal conditions, NPM-ALK phosphorylates the Y405 residue of STAT3, which causes the dimerization of phosphorylated STAT3 and its translocation into the nucleus where it modulates gene transcription in a methylation-dependent manner (18,19). This leads to the silencing of oncogenes such as STAT5A, IL-2 receptor gamma (IL-2Rg), Bcl-2-like protein 11 (BIM), protein tyrosine phosphatase non-receptor type 6 (SHP1), and CD48 (20)(21)(22)(23)(24)(25) and suppresses the expression of micro (mi)RNAs with oncogenic effects such as miR-150, miR-497, miR-21, miR-29a, miR-939, miR-96, miR-155, and miR-146a (26)(27)(28)(29)(30)(31). The consequent silencing of T-cell receptor-related genes including CD3ϵ, zeta-chain-associated protein kinase (ZAP)70, linker for activation of T cells (LAT), and SH2 domain-containing leukocyte protein of 76 kDa (SLP76) results in the loss of T cell identity (32).…”

Section: Signaling Pathways In Alk+ Alcl 21 Stat3 Pathwaymentioning

confidence: 99%

“…Given the reversibility and importance of epigenetic regulation of gene expression in the development of ALK+ ALCL, drugs targeting epigenetic modifications and allowing “re-expression of tumor suppressor proteins” or “reduced expression of oncogenic proteins”, such as DNA methylation, HDAC and SIN3A inhibitors, are a promising therapeutic approach. ( 20 , 22 , 23 , 30 , 31 , 33 ). In a multicenter clinical study of cidapenem in R/R PTCL, patients with ALK+ ALCL treated with cidapenem had a higher ORR (66.67%) and disease control rate (83.33%) and better prognosis compared to those with other PTCL subtypes ( 129 ).…”

Section: Strategies To Overcome Alk Tki Resistancementioning

confidence: 99%

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Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma

Wang

et al. 2022

Front. Oncol.

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Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase expressed at early stages of normal development and in various cancers including ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), in which it is the main therapeutic target. ALK tyrosine kinase inhibitors (ALK TKIs) have greatly improved the prognosis of ALK+ALCL patients, but the emergence of drug resistance is inevitable and limits the applicability of these drugs. Although various mechanisms of resistance have been elucidated, the problem persists and there have been relatively few relevant clinical studies. This review describes research progress on ALK+ ALCL including the application and development of new therapies, especially in relation to drug resistance. We also propose potential treatment strategies based on current knowledge to inform the design of future clinical trials.

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Section: Signaling Pathways In Alk+ Alcl 21 Stat3 Pathwaymentioning

confidence: 99%

Section: Strategies To Overcome Alk Tki Resistancementioning

confidence: 99%

Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma

Wang

et al. 2022

Front. Oncol.

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“…Post-transcriptional and post-translational mechanisms also influence c-Jun/JunB levels and activity. Recently, expression of miR-939 in ALK+ ALCL was found to reduce JunB levels [ 126 ], and JunB translation was promoted in ALK+ ALCL by targeting JunB mRNA to polysomes via a PI3K/Akt/mTor-dependent pathway [ 89 ]. There are several examples of the post-translational regulation of the AP-1 proteins in cHL and ALK+ ALCL.…”

Section: Multiple Mechanisms Account For Elevated Ap-1 Protein Expresmentioning

confidence: 99%

AP-1 family transcription factors: a diverse family of proteins that regulate varied cellular activities in classical hodgkin lymphoma and ALK+ ALCL

Nicoll

Ingham

2021

Exp Hematol Oncol

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Classical Hodgkin lymphoma (cHL) and anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma (ALK+ ALCL) are B and T cell lymphomas respectively, which express the tumour necrosis factor receptor superfamily member, CD30. Another feature shared by cHL and ALK+ ALCL is the aberrant expression of multiple members of the activator protein-1 (AP-1) family of transcription factors which includes proteins of the Jun, Fos, ATF, and Maf subfamilies. In this review, we highlight the varied roles these proteins play in the pathobiology of these lymphomas including promoting proliferation, suppressing apoptosis, and evading the host immune response. In addition, we discuss factors contributing to the elevated expression of these transcription factors in cHL and ALK+ ALCL. Finally, we examine therapeutic strategies for these lymphomas that exploit AP-1 transcriptional targets or the signalling pathways they regulate.

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“…The biological meaning of this effect is under investigation. Finally, as some microRNAs have been shown to have a role in ALCL [32,33], we analyzed their expression. A small but significant increase in miR-939 was detected only in Karpas-299 cells (Figure S11).…”

Section: Molecular Effects Of Combined Therapiesmentioning

confidence: 99%

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

Arosio

Sharma

Villa

et al. 2021

Cancers

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Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL.

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miR-939 acts as tumor suppressor by modulating JUNB transcriptional activity in pediatric anaplastic large cell lymphoma

Cited by 10 publications

References 13 publications

Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma

Holistic View of ALK TKI Resistance in ALK-Positive Anaplastic Large Cell Lymphoma

AP-1 family transcription factors: a diverse family of proteins that regulate varied cellular activities in classical hodgkin lymphoma and ALK+ ALCL

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma

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