Characterization of Copy Number Variations in Oral Cavity Squamous Cell Carcinoma Reveals a Novel Role for MLLT3 in Cell Invasiveness

Wang, Chun-I; Kao, Huang Kai; Chen, Ting-Wen; Huang, Yen‐Lin; Cheng, Hsing Wen; Yi, Jui Shan; Hung, Shao Yu; Wu, Chi-Sheng; Lee, Yun Shien; Chang, Kai Ping

doi:10.1634/theoncologist.2019-0063

Cited by 12 publications

(16 citation statements)

References 75 publications

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“…Moreover, it was shown that DOT1L participates in the upregulation of the cytoskeleton regulator RhoGTPase (RhoC) and of cIAP-2 and XIAP, belonging to the family of inhibitors of the apoptosis (IAPs), and facilitates invasion potential and cisplatin resistance of CD44v3 high ALDH1 high cells ( Bourguignon et al, 2016 ). In an additional study, amplification and upregulation of MLLT3 gene was found in oral cavity squamous cell carcinoma (OSCC) cells, where this gene has been involved in cell migration and invasion in conjunction with DOT1L association and regulation of CITED4 gene promoter and dysregulation of HIF-1α target genes TWIST , MMP1 , MMP2 , VIM , and CDH1 ( Wang C. I. et al, 2019 ).…”

Section: Mechanisms Of Dot1 Action In Solid Tumorsmentioning

confidence: 99%

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

et al. 2022

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The histone lysine methyltransferase DOT1L (DOT1-like histone lysine methyltransferase) is responsible for the epigenetic regulation of gene expression through specific methylation of lysine79 residue of histone H3 (H3K79) in actively transcribed genes. Its normal activity is crucial for embryonic development and adult tissues functions, whereas its aberrant functioning is known to contribute to leukemogenesis. DOT1L is the only lysine methyltransferase that does not contain a SET domain, which is a feature that allowed the development of selective DOT1L inhibitors that are currently investigated in Phase I clinical trials for cancer treatment. Recently, abnormal expression of this enzyme has been associated with poor survival and increased aggressiveness of several solid tumors. In this review evidences of aberrant DOT1L expression and activity in breast, ovarian, prostate, colon, and other solid tumors, and its relationships with biological and clinical behavior of the disease and response to therapies, are summarized. Current knowledge of the structural basis of DOT1L ability to regulate cell proliferation, invasion, plasticity and stemness, cell cycle progression, cell-to-cell signaling, epithelial-to-mesenchymal transition, and chemoresistance, through cooperation with several molecular partners including noncoding RNAs, is also reviewed. Finally, available options for the treatment of therapeutically challenging solid tumors by targeting DOT1L are discussed.

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Section: Mechanisms Of Dot1 Action In Solid Tumorsmentioning

confidence: 99%

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

et al. 2022

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“…Mutations in CBP and cofactor EP300 can significantly disrupt the overall CBP acetyltransferase activity, resulting in abnormal downregulation of target genes and leukaemia outbreak 12 . Furthermore, it has been demonstrated that abnormal copy number variation of transcriptional cofactors such as MLLT3 contributes to the overall activity of the oncogenic transcription complex 43 . More importantly, understanding these cofactor abnormalities provides therapeutic opportunities for blocking oncogenic TF transactivation.…”

Section: Discussionmentioning

confidence: 99%

Transcription factor 12‐mediated self‐feedback regulatory mechanism is required in DUX4 fusion leukaemia

Li,

Jiang,

Wang

et al. 2023

Clinical & Translational Med

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BackgroundIGH::DUX4 is frequently observed in 4% B‐cell acute lymphoblastic leukaemia patients. Regarding the IGH::DUX4‐driven transactivation and alternative splicing, which are the main reasons behind this acute leukaemia outbreak, it remains unclear how transcriptional cofactors contribute to this oncogenic process. Further investigation is required to elucidate their specific role in leukaemogenesis.MethodsIn order to investigate the cofactors of IGH::DUX4, integrated mining of Chromatin immunoprecipitation (ChIP)‐sequencing and RNA‐sequencing of leukaemia cells and patient samples were conducted. Furthermore, to elucidate the synergistic interaction between transcription factor 12 (TCF12) and IGH::DUX4, knockdown and knockout experiment, mammalian two‐hybridisation assay, co‐immunoprecipitation and in situ proximity ligation assays were carried out. Additionally, to further investigate the direct interaction between TCF12 and IGH::DUX4, AI‐based structural simulations were utilised. Finally, to validate the synergistic role of TCF12 in promoting IGH::DUX4 leukaemia, cell proliferation, apoptosis and drug sensitivity experiments were performed.ResultsIn this study, we observed that the IGH::DUX4 target gene TCF12 might be an important cofactor/helper for this oncogenic driver. The co‐expression of IGH::DUX4 and TCF12 resulted in enhanced DUX4‐driven transactivation. Supportively, knockdown and knockout of TCF12 significantly reduced expression of IGH::DUX4‐driven target genes in leukaemia REH (a precursor B‐cell leukaemia cell line) and NALM‐6 cells (a precursor B‐cell leukaemia cell line). Consistently, in TCF12 knockout cells, the expression of structure‐based TCF12 mutant, but not wild‐type TCF12, failed to restore the TCF12–IGH::DUX4 crosstalk and the synergistic transactivation. More importantly, the breakdown in TCF12–IGH::DUX4 cooperation impaired IGH::DUX4‐driven leukaemia cell survival, caused sensitivity to the chemotherapy.ConclusionsAltogether, these results helped to define a previously unrecognised TCF12‐mediated positive self‐feedback regulatory mechanism in IGH::DUX4 leukaemia, which holds the potential to function as a pivotal drug target for the management of this particular form of leukaemia.Highlights Transcription factor 12 (TCF12) is a new novel cofactor in IGH::DUX4 transcriptional complexes/machinery. TCF12 mediates a positive self‐feedback regulatory mechanism in IGH::DUX4‐driven oncogenic transaction. IGH::DUX4–TCF12 structure/cooperation might represent a potent target/direction in future drug design against B‐cell acute lymphoblastic leukaemia.

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“…14,15 In addition, MLLT3 mutations are associated with neurodevelopmental disease including mental retardation, epilepsy and ataxia, 16,17 and MLLT3 overexpression is associated with a poor prognosis in oral cavity squamous cell carcinoma. 18 MLLT3 is highly expressed in hematopoietic stem cells (HSCs) and erythroid/megakaryocytic (E/Meg) compartments in humans and in mice. 19,20 Previous in-vitro studies documented an essential role of MLLT3 in HSC stemness maintenance 21 and erythroid/megakaryocytic (E/Meg) lineage decisions.…”

Section: Introductionmentioning

confidence: 99%

“…The two genes are involved in a reciprocal in‐frame translocation—t(9;11)(p22;q23)—resulting in an oncogenic KMT2A‐MLLT3 fusion protein, which induces leukemia transformation in murine models 14,15 . In addition, MLLT3 mutations are associated with neurodevelopmental disease including mental retardation, epilepsy and ataxia, 16,17 and MLLT3 overexpression is associated with a poor prognosis in oral cavity squamous cell carcinoma 18 …”

Section: Introductionmentioning

confidence: 99%

Leukemia‐associated transcription factor mllt3 is important for primitive erythroid development in zebrafish embryogenesis

Germanò

Porazzi

Felix

2022

Developmental Dynamics

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Background: MLLT3 (AF9) is a nuclear transcription factor crucial for hematopoietic stem cell and progenitor cell maintenance, but its role during embryonic hematopoiesis remains uncertain. Here, we examine the role of mllt3 in developmental hematopoiesis during embryogenesis using zebrafish.Results: Cloning, sequencing, phylogenetic, and synteny analyses showed high evolutionary conservation between important functional domains of the zebrafish orthologue of mllt3 and MLLT3 in humans. Quantitative reverse transcription-PCR and in situ hybridization analyses revealed that mllt3 is maternally supplied and zygotically expressed throughout embryonic development, and that expression is highest between 10 and 24 hours postfertilization (hpf) coincident with enrichment in the intermediate cell mass (ICM) and posterior blood island, which are the sites of the primitive and transient definitive hematopoiesis in zebrafish, respectively. Further, we found co-expression of mllt3 with the early hematopoietic progenitor markers tal1, gata2, and gata1a in the posterior ICM. By investigating zebrafish hematopoietic mutants, we discovered that mllt3 is involved in erythroid precursor formation. By 48-72 hpf, mllt3 expression proved to be restricted to non-hematopoietic tissues including head structures, pronephric tubules, and liver primordium. Conclusions: These findings establish a link between mllt3 and primitive erythropoiesis and provide the basis for future functional investigations.

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Characterization of Copy Number Variations in Oral Cavity Squamous Cell Carcinoma Reveals a Novel Role for MLLT3 in Cell Invasiveness

Cited by 12 publications

References 75 publications

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors

Transcription factor 12‐mediated self‐feedback regulatory mechanism is required in DUX4 fusion leukaemia

Leukemia‐associated transcription factor mllt3 is important for primitive erythroid development in zebrafish embryogenesis

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