The cancer COMPASS: navigating the functions of MLL complexes in cancer

Ford, David J.; Dingwall, Andrew K.

doi:10.1016/j.cancergen.2015.01.005

Cited by 123 publications

(131 citation statements)

References 177 publications

(126 reference statements)

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“…Several lines of evidence, however, suggest that KMT2D might also exhibit oncogenic properties for various tumors. It is overexpressed in breast and colon carcinomas, where it is associated with poor prognosis, whereas its silencing signifi cantly reduces migration in colorectal and breast cancer cell lines and growth in a mouse xenograft of bladder cancer ( 20 ). We showed here that KMT2D depletion reduces cell migration and inhibits in vivo growth of NRAS -mutated melanomas.…”

Section: Discussionmentioning

confidence: 67%

“…KMT2D is frequently mutated in a variety of cancers ( 20 ). Most cancer-associated KMT2D mutations are frameshift and nonsense alterations, suggesting that KMT2D functions as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

“…KMT2D predominantly promotes H3K4 monomethylation (H3K4me1) at adipocyte-, myocyte-, and macrophage-specifi c enhancers, and transcriptome changes during adipogenesis and transdifferentiation of preadipocytes into myocytes ( 20,22,28 ).…”

Section: Kmt2d Regulates Enhancer Activity In the Patients With Melanomamentioning

confidence: 99%

“…1C [18][19][20][21][22] by a conventional "single-shRNA" in vivo approach. Three were positive hits in all three melanomas ( BAZ1B, SMARCA4, CHD4 ), whereas the fourth ( KMT2D ) was positive only in the two NRAS -mutated melanomas.…”

Section: Validation Of the Epigenetic Shrna Screensmentioning

confidence: 99%

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In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

et al. 2016

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The identifi cation of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the fi rst in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specifi c shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth ( ∼ 50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identifi ed genes, the Histone-lysine N-methyltransferase KMT2D , and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specifi c, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways. SIGNIFICANCE:Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specifi c signaling pathways are activated in tumors. Cancer Discov;6(6);

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Kmt2d Regulates Enhancer Activity In the Patients With Melanomamentioning

confidence: 99%

Section: Validation Of the Epigenetic Shrna Screensmentioning

confidence: 99%

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In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

et al. 2016

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“…The MLL/Set1 gene family of histone lysine methyltransferases (aka KMT2 family) codes for subunits of large multimeric complexes, referred to as Set1/COMPASS-like complexes [142]. The COMPASS (COMplex of Proteins ASsociated with Set1) complexes are able to methylate H3K4, a histone modification associated with active transcription, catalyzed by the set domain of the MLL proteins.…”

Section: Deregulation Of Histone Methylation In Cllmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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The Role of Epigenetic Dysregulation in Lymphoma Biology

Deng and,

Green

2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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The cancer COMPASS: navigating the functions of MLL complexes in cancer

Cited by 123 publications

References 177 publications

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype

Chronic lymphocytic leukemia: Time to go past genomics?

The Role of Epigenetic Dysregulation in Lymphoma Biology

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