Ectopic Expression of the Histone Methyltransferase Ezh2 in Haematopoietic Stem Cells Causes Myeloproliferative Disease

Overview

Journal Nat Commun

Specialty Biology

Date 2012 Jan 12

PMID 22233633

Citations 68

Authors

A Herrera-Merchan

L Arranz

J M Ligos

A de Molina

O Dominguez

S Gonzalez

Affiliations

Soon will be listed here.

Abstract

Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self-renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gain-of-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and Ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies.

Citing Articles

a novel marker associated with poor pediatric AML outcomes that affect the fatty acid synthesis and cell cycle pathways.

Bakhtiari M, Jordan S, Mumme H, Sharma R, Shanmugam M, Bhasin S Front Oncol. 2024; 14:1445173.

PMID: 39703843 PMC: 11655347. DOI: 10.3389/fonc.2024.1445173.

Functions and regulatory mechanisms of resting hematopoietic stem cells: a promising targeted therapeutic strategy.

Tang X, Wang Z, Wang J, Cui S, Xu R, Wang Y Stem Cell Res Ther. 2023; 14(1):73.

PMID: 37038215 PMC: 10088186. DOI: 10.1186/s13287-023-03316-5.

Stage-specific dual function: EZH2 regulates human erythropoiesis by eliciting histone and non-histone methylation.

Li M, Liu D, Xue F, Zhang H, Yang Q, Sun L Haematologica. 2023; 108(9):2487-2502.

PMID: 37021526 PMC: 10483364. DOI: 10.3324/haematol.2022.282016.

Dissecting and targeting noncanonical functions of EZH2 in multiple myeloma via an EZH2 degrader.

Yu X, Wang J, Gong W, Ma A, Shen Y, Zhang C Oncogene. 2023; 42(13):994-1009.

PMID: 36747009 PMC: 10040430. DOI: 10.1038/s41388-023-02618-5.

Autologous treatment for ALS with implication for broad neuroprotection.

Kim D, Kim S, Sung A, Patel N, Wong N, Conboy M Transl Neurodegener. 2022; 11(1):16.

PMID: 35272709 PMC: 8915496. DOI: 10.1186/s40035-022-00290-5.

References

Ogilvy S, Metcalf D, Gibson L, Bath M, Harris A, Adams J . Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment. Blood. 1999; 94(6):1855-63. View

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

Croker B, Metcalf D, Robb L, Wei W, Mifsud S, DiRago L . SOCS3 is a critical physiological negative regulator of G-CSF signaling and emergency granulopoiesis. Immunity. 2004; 20(2):153-65. DOI: 10.1016/s1074-7613(04)00022-6. View

Xu F, Li X, Wu L, Zhang Q, Yang R, Yang Y . Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Ann Hematol. 2010; 90(6):643-53. DOI: 10.1007/s00277-010-1128-5. View

Nikoloski G, Langemeijer S, Kuiper R, Knops R, Massop M, Tonnissen E . Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat Genet. 2010; 42(8):665-7. DOI: 10.1038/ng.620. View

Margueron R, Reinberg D . The Polycomb complex PRC2 and its mark in life. Nature. 2011; 469(7330):343-9. PMC: 3760771. DOI: 10.1038/nature09784. View

Sneeringer C, Scott M, Kuntz K, Knutson S, Pollock R, Richon V . Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010; 107(49):20980-5. PMC: 3000297. DOI: 10.1073/pnas.1012525107. View

Herrera-Merchan A, Cerrato C, Luengo G, Dominguez O, Piris M, Serrano M . miR-33-mediated downregulation of p53 controls hematopoietic stem cell self-renewal. Cell Cycle. 2010; 9(16):3277-85. DOI: 10.4161/cc.9.16.12598. View

Akala O, Clarke M . Hematopoietic stem cell self-renewal. Curr Opin Genet Dev. 2006; 16(5):496-501. DOI: 10.1016/j.gde.2006.08.011. View

10.

Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K . Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004; 118(2):149-61. DOI: 10.1016/j.cell.2004.07.004. View

11.

Clausen B, Burkhardt C, Reith W, Renkawitz R, Forster I . Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 2000; 8(4):265-77. DOI: 10.1023/a:1008942828960. View

12.

Martin-Perez D, Piris M, Sanchez-Beato M . Polycomb proteins in hematologic malignancies. Blood. 2010; 116(25):5465-75. DOI: 10.1182/blood-2010-05-267096. View

13.

Lund A, van Lohuizen M . Polycomb complexes and silencing mechanisms. Curr Opin Cell Biol. 2004; 16(3):239-46. DOI: 10.1016/j.ceb.2004.03.010. View

14.

Gonzalez S, Pisano D, Serrano M . Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs. Cell Cycle. 2008; 7(16):2601-8. DOI: 10.4161/cc.7.16.6541. View

15.

de Boer J, Williams A, Skavdis G, Harker N, Coles M, Tolaini M . Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur J Immunol. 2003; 33(2):314-25. DOI: 10.1002/immu.200310005. View

16.

Forsberg E, Passegue E, Prohaska S, Wagers A, Koeva M, Stuart J . Molecular signatures of quiescent, mobilized and leukemia-initiating hematopoietic stem cells. PLoS One. 2010; 5(1):e8785. PMC: 2808351. DOI: 10.1371/journal.pone.0008785. View

17.

Sauvageau M, Sauvageau G . Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell. 2010; 7(3):299-313. PMC: 4959883. DOI: 10.1016/j.stem.2010.08.002. View

18.

Ohm J, McGarvey K, Yu X, Cheng L, Schuebel K, Cope L . A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet. 2007; 39(2):237-42. PMC: 2744394. DOI: 10.1038/ng1972. View

19.

Ashburner M, Ball C, Blake J, Botstein D, Butler H, Cherry J . Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000; 25(1):25-9. PMC: 3037419. DOI: 10.1038/75556. View

20.

Goodell M, Brose K, Paradis G, Conner A, Mulligan R . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996; 183(4):1797-806. PMC: 2192511. DOI: 10.1084/jem.183.4.1797. View