COMPASS Ascending: Emerging Clues Regarding the Roles of MLL3/KMT2C and MLL2/KMT2D Proteins in Cancer

Overview

Journal Cancer Lett

Specialty Oncology

Date 2019 May 26

PMID 31128216

Citations 88

Authors

Richard J Fagan

Andrew K Dingwall

Affiliations

Soon will be listed here.

Abstract

The KMT2 (lysine methyltransferase) family of histone modifying proteins play essential roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many blood and solid tumor cancers. The KMT2A-D proteins are histone 3 lysine 4 (H3K4) methyltransferases embedded in large COMPASS-like complexes important for RNA Polymerase II-dependent transcription. KMT2 mutations were initially associated with pediatric Mixed Lineage Leukemias (MLL) and found to be the result of rearrangements of the MLL1/KMT2A gene at 11q23. Over the past several years, large-scale tumor DNA sequencing studies have revealed the potential involvement of other KMT2 family genes, including heterozygous somatic mutations in the paralogous MLL3/KMT2C and MLL2(4)/KMT2D genes that are now among the most frequently associated with human cancer. Recent studies have provided a better understanding of the potential roles of disrupted KMT2C and KMT2D family proteins in cell growth aberrancy. These findings, together with an examination of cancer genomics databases provide new insights into the contribution of KMT2C/D proteins in epigenetic gene regulation and links to carcinogenesis.

Citing Articles

Enhancer reprogramming: critical roles in cancer and promising therapeutic strategies.

Yang J, Zhou F, Luo X, Fang Y, Wang X, Liu X Cell Death Discov. 2025; 11(1):84.

PMID: 40032852 PMC: 11876437. DOI: 10.1038/s41420-025-02366-3.

Secernin-2 Stabilizes Histone Methyltransferase KMT2C to Suppress Progression and Confer Therapeutic Sensitivity to PARP Inhibition in Triple-Negative Breast Cancer.

Huang M, Cai J, Yang S, Zhao Q, Shao Z, Zhang F Adv Sci (Weinh). 2025; 12(10):e2413280.

PMID: 39836524 PMC: 11905051. DOI: 10.1002/advs.202413280.

Clonal evolution defines risk stratification for central nervous system leukemia in adult acute lymphoblastic leukemia.

Li J, Chen J, Wang Q, Ou J, Huang Z, Deng S Ann Hematol. 2024; 103(12):5759-5767.

PMID: 39609281 DOI: 10.1007/s00277-024-06116-w.

KMT2A facilitates the epithelial-to-mesenchymal transition and the progression of ovarian cancer.

Zhu Y, Jiang S, Tang R, Chen H, Jia G, Zhou X Mol Cell Biochem. 2024; .

PMID: 39589456 DOI: 10.1007/s11010-024-05167-x.

Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities.

Takemon Y, Pleasance E, Gagliardi A, Hughes C, Csizmok V, Wee K Genome Med. 2024; 16(1):136.

PMID: 39578878 PMC: 11583415. DOI: 10.1186/s13073-024-01401-9.

References

Ayton P, Sneddon S, Palmer D, Rosewell I, Owen M, Young B . Truncation of the Mll gene in exon 5 by gene targeting leads to early preimplantation lethality of homozygous embryos. Genesis. 2001; 30(4):201-12. DOI: 10.1002/gene.1066. View

Xia Z, Anderson M, Diaz M, Zeleznik-Le N . MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein. Proc Natl Acad Sci U S A. 2003; 100(14):8342-7. PMC: 166231. DOI: 10.1073/pnas.1436338100. View

Sedkov Y, Cho E, Petruk S, Cherbas L, Smith S, Jones R . Methylation at lysine 4 of histone H3 in ecdysone-dependent development of Drosophila. Nature. 2003; 426(6962):78-83. PMC: 2743927. DOI: 10.1038/nature02080. View

Slany R . When epigenetics kills: MLL fusion proteins in leukemia. Hematol Oncol. 2005; 23(1):1-9. DOI: 10.1002/hon.739. View

Feinberg A, Ohlsson R, Henikoff S . The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2005; 7(1):21-33. DOI: 10.1038/nrg1748. View

Glaser S, Schaft J, Lubitz S, Vintersten K, van der Hoeven F, Tufteland K . Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development. 2006; 133(8):1423-32. DOI: 10.1242/dev.02302. View

Qian C, Zhou M . SET domain protein lysine methyltransferases: Structure, specificity and catalysis. Cell Mol Life Sci. 2006; 63(23):2755-63. PMC: 11136235. DOI: 10.1007/s00018-006-6274-5. View

Krivtsov A, Armstrong S . MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer. 2007; 7(11):823-33. DOI: 10.1038/nrc2253. View

Ding L, Getz G, Wheeler D, Mardis E, McLellan M, Cibulskis K . Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008; 455(7216):1069-75. PMC: 2694412. DOI: 10.1038/nature07423. View

10.

Bach C, Mueller D, Buhl S, Garcia-Cuellar M, Slany R . Alterations of the CxxC domain preclude oncogenic activation of mixed-lineage leukemia 2. Oncogene. 2008; 28(6):815-23. DOI: 10.1038/onc.2008.443. View

11.

Compagno M, Lim W, Grunn A, Nandula S, Brahmachary M, Shen Q . Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 2009; 459(7247):717-21. PMC: 2973325. DOI: 10.1038/nature07968. View

12.

Lee J, Kim D, Lee S, Yang Q, Lee D, Lee S . A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4. Proc Natl Acad Sci U S A. 2009; 106(21):8513-8. PMC: 2689008. DOI: 10.1073/pnas.0902873106. View

13.

Natarajan T, Kallakury B, Sheehan C, Bartlett M, Ganesan N, Preet A . Epigenetic regulator MLL2 shows altered expression in cancer cell lines and tumors from human breast and colon. Cancer Cell Int. 2010; 10:13. PMC: 2878298. DOI: 10.1186/1475-2867-10-13. View

14.

Cheung K, Johnson N, Affleck J, Severson T, Steidl C, Ben-Neriah S . Acquired TNFRSF14 mutations in follicular lymphoma are associated with worse prognosis. Cancer Res. 2010; 70(22):9166-74. DOI: 10.1158/0008-5472.CAN-10-2460. View

15.

Parsons D, Li M, Zhang X, Jones S, Leary R, Cheng-Ho Lin J . The genetic landscape of the childhood cancer medulloblastoma. Science. 2010; 331(6016):435-9. PMC: 3110744. DOI: 10.1126/science.1198056. View

16.

Morin R, Mendez-Lago M, Mungall A, Goya R, Mungall K, Corbett R . Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011; 476(7360):298-303. PMC: 3210554. DOI: 10.1038/nature10351. View

17.

Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A . Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011; 43(9):830-7. PMC: 3297422. DOI: 10.1038/ng.892. View

18.

Mohan M, Herz H, Smith E, Zhang Y, Jackson J, Washburn M . The COMPASS family of H3K4 methylases in Drosophila. Mol Cell Biol. 2011; 31(21):4310-8. PMC: 3209330. DOI: 10.1128/MCB.06092-11. View

19.

Kim D, Kim J, Lee J . Requirement for MLL3 in p53 regulation of hepatic expression of small heterodimer partner and bile acid homeostasis. Mol Endocrinol. 2011; 25(12):2076-83. PMC: 3231838. DOI: 10.1210/me.2011-1198. View

20.

Greer E, Shi Y . Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet. 2012; 13(5):343-57. PMC: 4073795. DOI: 10.1038/nrg3173. View