Super-Enhancers Dysregulations in Hematological Malignancies
Tóm tắt
Hematological malignancies affecting either the lymphoid or the myeloid lineages involve epigenetic mutations or dysregulation in the majority of cases. These epigenetic abnormalities can affect regulatory elements in the genome and, particularly, enhancers. Recently, large regulatory elements known as super-enhancers, initially identified for their critical roles in cell-type specific expression regulation of genes controlling cell identity, have been shown to also be involved in tumorigenesis in many cancer types and hematological malignancies via the regulation of numerous oncogenes, including MYC. In this review, we highlight the existing links between super-enhancers and hematological malignancies, with a particular focus on acute myeloid leukemia, a clonal hematopoietic neoplasm with dismal outcomes, resulting in an uncontrolled proliferation of myeloblasts, abnormally blocked during differentiation and accumulating within the patient’s bone marrow. We report recent works, performed during the last few years, treating this subject and consider the possibility of targeting oncogenic regulatory elements, as well as the effectiveness and limitations reported so far for such strategies.
Từ khóa
Tài liệu tham khảo
Papaemmanuil, 2016, Genomic classification and prognosis in acute myeloid leukemia, N. Engl. J. Med., 374, 2209, 10.1056/NEJMoa1516192
Nakao, 1996, Internal tandem duplication of the flt3 gene found in acute myeloid leukemia, Leukemia, 10, 1911
Falini, 2005, Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype, N. Engl. J. Med., 352, 254, 10.1056/NEJMoa041974
Mardis, 2009, Recurring mutations found by sequencing an acute myeloid leukemia genome, N. Engl. J. Med., 361, 1058, 10.1056/NEJMoa0903840
Ward, 2010, The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting α-ketoglutarate to 2-hydroxyglutarate, Cancer Cell, 17, 225, 10.1016/j.ccr.2010.01.020
Renshaw, 1996, Mutations in the Wilms’ tumor gene WT1 in leukemias, Blood, 87, 2171, 10.1182/blood.V87.6.2171.bloodjournal8762171
Zhang, 2019, Mutations in EZH2 are associated with poor prognosis for patients with myeloid neoplasms, Genes Dis., 6, 276, 10.1016/j.gendis.2019.05.001
Kirito, 2008, A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies, Haematologica, 93, 155, 10.3324/haematol.12050
Ley, 2008, DNA sequencing of a cytogenetically normal acute myeloid leukemia genome, Nature, 456, 66, 10.1038/nature07485
Vlierberghe, 2011, PHF6 mutations in adult acute myeloid leukemia, Leukemia, 25, 130, 10.1038/leu.2010.247
Spensberger, 2005, Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia, Oncogene, 24, 4129, 10.1038/sj.onc.1208588
Patel, 2012, Prognostic relevance of integrated genetic profiling in acute myeloid leukemia, N. Engl. J. Med., 366, 1079, 10.1056/NEJMoa1112304
Delhommeau, 2009, Mutation inTET2in myeloid cancers, N. Engl. J. Med., 360, 2289, 10.1056/NEJMoa0810069
Elhefni, 2011, The prognostic impact of K-RAS mutations in adult acute myeloid leukemia patients treated with high-dose cytarabine, OncoTargets Ther., 4, 115, 10.2147/OTT.S12602
Ding, 2012, Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing, Nature, 481, 506, 10.1038/nature10738
Martens, 2010, The molecular signature of oncofusion proteins in acute myeloid leukemia, FEBS Lett., 584, 2662, 10.1016/j.febslet.2010.04.002
Alcalay, 2003, Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair, J. Clin. Investig., 112, 1751, 10.1172/JCI17595
Cancer Genome Atlas Research Network, Ley, T.J., Miller, C., Ding, L., Raphael, B.J., Mungall, A.J., Robertson, A.G., Hoadley, K., Triche, T.J., and Laird, P.W. (2013). Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med., 368, 2059–2074.
Calo, 2013, Modification of enhancer chromatin: What, how, and why?, Mol. Cell, 49, 825, 10.1016/j.molcel.2013.01.038
Mora, 2016, In the loop: Promoter–enhancer interactions and bioinformatics, Brief. Bioinform., 17, 980
Barolo, 2012, Shadow enhancers: Frequently asked questions about distributed cis-regulatory information and enhancer redundancy, Bioessays, 34, 135, 10.1002/bies.201100121
Hnisz, 2013, Super-enhancers in the control of cell identity and disease, Cell, 155, 934, 10.1016/j.cell.2013.09.053
Whyte, 2013, Master transcription factors and mediator establish super-enhancers at key cell identity genes, Cell, 153, 307, 10.1016/j.cell.2013.03.035
Witte, S., Bradley, A., Enright, A.J., and Muljo, S.A. (2015). High-density P300 enhancers control cell state transitions. BMC Genom., 16.
Wu, 2019, From super-enhancer non-coding RNA to immune checkpoint: Frameworks to functions, Front. Oncol., 9, 1307, 10.3389/fonc.2019.01307
Bahr, 2018, A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies, Nature, 553, 515, 10.1038/nature25193
Yassin, 2019, A novel method for detecting the cellular stemness state in normal and leukemic human hematopoietic cells can predict disease outcome and drug sensitivity, Leukemia, 33, 2061, 10.1038/s41375-019-0386-z
Thirant, 2017, ETO2-GLIS2 hijacks transcriptional complexes to drive cellular identity and self-renewal in pediatric acute megakaryoblastic leukemia, Cancer Cell, 31, 452, 10.1016/j.ccell.2017.02.006
Wang, 2016, MED12 regulates HSC-specific enhancers independently of mediator kinase activity to control hematopoiesis, Cell Stem Cell, 19, 784, 10.1016/j.stem.2016.08.004
Zhou, 2015, Epstein-barr virus oncoprotein super-enhancers control B cell growth, Cell Host Microbe, 17, 205, 10.1016/j.chom.2014.12.013
Mansour, 2014, An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element, Science, 346, 1373, 10.1126/science.1259037
Duboule, 2013, Topology of mammalian developmental enhancers and their regulatory landscapes, Nature, 502, 499, 10.1038/nature12753
Pombo, 2015, Three-dimensional genome architecture: Players and mechanisms, Nat. Rev. Mol. Cell Biol., 16, 245, 10.1038/nrm3965
Bulger, 2011, Functional and mechanistic diversity of distal transcription enhancers, Cell, 144, 327, 10.1016/j.cell.2011.01.024
Uhlmann, 2016, SMC complexes: From DNA to chromosomes, Nat. Rev. Mol. Cell Biol., 17, 399, 10.1038/nrm.2016.30
Nora, 2017, Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization, Cell, 169, 930, 10.1016/j.cell.2017.05.004
Alipour, 2012, Self-organization of domain structures by DNA-loop-extruding enzymes, Nucleic Acids Res., 40, 11202, 10.1093/nar/gks925
Kim, 2019, Human cohesin compacts DNA by loop extrusion, Science, 366, 1345, 10.1126/science.aaz4475
Li, 2016, Enhancers as non-coding RNA transcription units: Recent insights and future perspectives, Nat. Rev. Genet., 17, 207, 10.1038/nrg.2016.4
Khan, 2018, Super-enhancers are transcriptionally more active and cell type-specific than stretch enhancers, Epigenetics, 13, 910, 10.1080/15592294.2018.1514231
Shin, 2016, Hierarchy within the mammary STAT5-driven Wap super-enhancer, Nat. Genet., 48, 904, 10.1038/ng.3606
Dukler, 2017, Is a super-enhancer greater than the sum of its parts?, Nat. Genet., 49, 2, 10.1038/ng.3759
Hay, 2016, Genetic dissection of the α-globin super-enhancer in vivo, Nat. Genet., 48, 895, 10.1038/ng.3605
Abraham, 2017, Small genomic insertions form enhancers that misregulate oncogenes, Nat. Commun., 8, 14385, 10.1038/ncomms14385
Hnisz, 2016, Activation of proto-oncogenes by disruption of chromosome neighborhoods, Science, 351, 1454, 10.1126/science.aad9024
Flavahan, 2019, Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs, Nature, 575, 229, 10.1038/s41586-019-1668-3
Yoshida, 2013, The landscape of somatic mutations in Down syndrome–related myeloid disorders, Nat. Genet., 45, 1293, 10.1038/ng.2759
Zhang, 2015, Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers, Nat. Genet., 48, 176, 10.1038/ng.3470
Herranz, 2014, N-Me, a long range oncogenic enhancer in T-cell acute lymphoblastic leukemia, Nat. Med., 20, 1130, 10.1038/nm.3665
Shi, 2013, Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation, Genes Dev., 27, 2648, 10.1101/gad.232710.113
Kubota, 2019, Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm, Nat. Commun., 10, 1653, 10.1038/s41467-019-09710-z
Sanders, 2014, A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia, Cell, 157, 369, 10.1016/j.cell.2014.02.019
Walker, 2014, Translocations at 8q24 juxtapose MYC with genes that harbor superenhancers resulting in overexpression and poor prognosis in myeloma patients, Blood Cancer J., 4, e191, 10.1038/bcj.2014.13
Affer, 2014, Promiscuous rearrangements of the MYC locus hijack enhancers and super-enhancers to dysregulate MYC Expression in multiple myeloma, Leukemia, 28, 1725, 10.1038/leu.2014.70
Drier, 2016, An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma, Nat. Genet., 48, 265, 10.1038/ng.3502
Katerndahl, 2017, Antagonism of B cell enhancer networks by STAT5 drives leukemia and poor patient survival, Nat. Immunol., 18, 694, 10.1038/ni.3716
Ottema, 2021, The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops, Nat. Commun., 12, 5679, 10.1038/s41467-021-25862-3
Benbarche, 2022, Screening of ETO2-GLIS2 induced Super Enhancers identifies targetable cooperative dependencies in acute megakaryoblastic leukemia, Sci Adv., 8, eabg9455, 10.1126/sciadv.abg9455
Tian, 2018, AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer, J. Cell. Biochem., 119, 3706, 10.1002/jcb.26587
Smeenk, 2021, Selective requirement of MYB for oncogenic hyperactivation of a translocated enhancer in leukemia, Cancer Discov., 11, 2868, 10.1158/2159-8290.CD-20-1793
Tulstrup, 2021, TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis, Nat. Commun., 12, 6061, 10.1038/s41467-021-26093-2
Rasmussen, 2019, TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells, Genome Res., 29, 564, 10.1101/gr.239277.118
Rasmussen, 2015, Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis, Genes Dev., 29, 910, 10.1101/gad.260174.115
Dooley, 2016, Tandemly integrated HPV16 can form a Brd4-dependent super-enhancer-like element that drives transcription of viral oncogenes, mBio, 7, e01446, 10.1128/mBio.01446-16
Weinstein, 2006, Mechanisms of Disease: Oncogene addiction—a rationale for molecular targeting in cancer therapy, Nat. Clin. Pr. Oncol., 3, 448, 10.1038/ncponc0558
Hoke, 2013, Selective inhibition of tumor oncogenes by disruption of super-enhancers, Cell, 153, 320, 10.1016/j.cell.2013.03.036
Chapuy, 2013, Discovery and characterization of super-enhancer-associated dependencies in diffuse large B cell lymphoma, Cancer Cell, 24, 777, 10.1016/j.ccr.2013.11.003
Hajmirza, A., Emadali, A., Gauthier, A., Casasnovas, O., Gressin, R., and Callanan, M.B. (2018). BET family protein BRD4: An emerging actor in NFκB signaling in inflammation and cancer. Biomedicines, 6.
Zuber, 2011, RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia, Nature, 478, 524, 10.1038/nature10334
Delmore, 2011, BET bromodomain inhibition as a therapeutic strategy to target c-Myc, Cell, 146, 904, 10.1016/j.cell.2011.08.017
Mertz, 2011, Targeting MYC dependence in cancer by inhibiting BET bromodomains, Proc. Natl. Acad. Sci. USA, 108, 16669, 10.1073/pnas.1108190108
Donati, 2018, BRD4 and Cancer: Going beyond transcriptional regulation, Mol. Cancer, 17, 164, 10.1186/s12943-018-0915-9
Nilson, 2015, THZ1 reveals roles for Cdk7 in co-transcriptional capping and pausing, Mol. Cell, 59, 576, 10.1016/j.molcel.2015.06.032
Sampathi, 2019, The CDK7 inhibitor THZ1 alters RNA polymerase dynamics at the 5′ and 3′ ends of genes, Nucleic Acids Res., 47, 3921, 10.1093/nar/gkz127
Chipumuro, 2014, CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer, Cell, 159, 1126, 10.1016/j.cell.2014.10.024
Kwiatkowski, 2014, Targeting transcription regulation in cancer with a covalent CDK7 inhibitor, Nature, 511, 616, 10.1038/nature13393
Elyada, 2011, CKIα ablation highlights a critical role for p53 in invasiveness control, Nature, 470, 409, 10.1038/nature09673
Minzel, 2018, Small molecules co-targeting CKIα and the transcriptional kinases CDK7/9 control AML in preclinical models, Cell, 175, 171, 10.1016/j.cell.2018.07.045
Rathert, 2015, Transcriptional plasticity promotes primary and acquired resistance to BET inhibition, Nature, 525, 543, 10.1038/nature14898
Guo, 2020, A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells, Nat. Commun., 11, 740, 10.1038/s41467-020-14604-6
Call, 2020, Targeting oncogenic super enhancers in MYC-dependent AML using a small molecule activator of NR4A nuclear receptors, Sci. Rep., 10, 2851, 10.1038/s41598-020-59469-3
Bakshi, 2018, Toxicity of JQ1 in neuronal derivatives of human umbilical cord mesenchymal stem cells, Oncotarget, 9, 33853, 10.18632/oncotarget.26127
Alghamdi, 2016, BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells, Stem Cell Res. Ther., 7, 22, 10.1186/s13287-016-0278-3
Matzuk, 2012, Small-molecule inhibition of BRDT for male contraception, Cell, 150, 673, 10.1016/j.cell.2012.06.045
Berthon, 2016, Bromodomain inhibitor OTX015 in patients with acute leukaemia: A dose-escalation, phase 1 study, Lancet Haematol., 3, e186, 10.1016/S2352-3026(15)00247-1