Page 71 - Haematologica April 2020

RUNX3 in aging and erythroid-myeloid balance
and the aberrant retention of GMP markers such as CD123 and CD45RA on RUNX3 deficient cells suggests an additional role in lineage resolution. Taken together, the current findings implicate RUNX3 in the maintenance of bone marrow lineage balance and identify its decline in aged HSPC as a likely contributory factor in aging-associ- ated anemias.
Acknowledgments
Thank you to Nicole Brimer for providing the packaging plas- mids for production of retroviral particles. Thank you to Joanne Lannigan, Michael Solga, Claude Chew, Alexander Wendling, and Lesa Campbell for assistance with flow cytometry experi-
ments at the University of Virginia Flow Core Facility. Thank you to Pat Pramoonjago and Rebecca Blackwell for assistance with immunohistochemistry experiments at the Biorepository and Tissue Research Facility. Thank you to Janet Cross, Michael McConnell, John Bushweller and Mazhar Adli for project guid- ance and discussion.
Funding
This work was funded by the following NIH grants: R01 HL130550, R01 DK079924, R01 DK101550. PB was sup- ported in part by grant NIH T32 CA009109-39 (Cancer Research Training in Molecular Biology) awarded to the University of Virginia.
References
1. Choudry FA, Frontini M. Epigenetic Control of Haematopoietic Stem Cell Aging and Its Clinical Implications. Stem Cells Int. 2016;2016:5797521.
2. Akunuru S, Geiger H. Aging, Clonality and Rejuvination of Hematopoietic Stem Cells. Trends Mol Med. 2016;22(8):701-712.
3. Sun D, Luo M, Jeong M, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that rein- force self-renewal. Cell Stem Cell. 2014; 14(5):673-688.
4. PangWW,PriceEa,SahooD,etal.Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc Natl Acad Sci. 2011; 108(50):20012-20017.
5. Xing Z, Ryan MA, Daria D, et al. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2012;108(7):2190-2197.
6. Beerman I, Bock C, Garrison BS, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013;12(4):413-425.
7. Rossi DJ, Bryder D, Zahn JM, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005;102(26):9194-9199.
8. Yamamoto R, Wilkinson AC, Ooehara J, et al. Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment. Cell Stem Cell. 2018; 22(4):600-607.
9. Maryanovich M, Zahalka AH, Pierce H, et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med. 2018;24(6):782- 791.
10. Chi XZ, Lee JW, Lee YS, Park IY, Ito Y, Bae SC. Runx3 plays a critical role in restriction- point and defense against cellular transfor- mation. Oncogene. 2017;36(50):6884-6894.
11. Krishnan V, Chong YL, Tan TZ, et al. TGF promotes genomic instability after loss of RUNX3. Cancer Res. 2018;78(1):88-102.
12. Fainaru O, Woolf E, Lotem J, et al. Runx3 regulates mouse TGF-??-mediated dendrit- ic cell function and its absence results in air- way inflammation. EMBO J. 2004; 23(4):969-979.
13. Ebihara T, Song C, Ryu SH, et al. Runx3 specifies lineage commitment of innate lymphoid cells. Nat Immunol. 2015; 16(11):1124-1133.
14. InoueKI,ShigaT,ItoY.Runxtranscription factors in neuronal development. Neural Dev. 2008;3(1):1-7.
15. Meng G, Zhong X, Mei H. A systematic investigation into Aging Related Genes in Brain and Their Relationship with Alzheimer’s Disease. PLoS One. 2016;11(3):1-17.
16. So K, Tamura G, Honda T, et al. Multiple tumor suppressor genes are increasingly methylated with age in non-neoplastic gas- tric epithelia. Cancer Sci. 2006;97(11):1155- 1158.
17. Tserel L, Kolde R, Limbach M, et al. Age- related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes. Sci Rep. 2015;5:13107.
18. Wolff EM, Liang G, Cortez CC, et al. RUNX3 methylation reveals that bladder tumors are older in patients with a history of smoking. Cancer Res. 2008;68(15):6208- 6214.
19. Kalev-Zylinska ML, Horsfield JA, Flores MVC, et al. Runx3 Is Required for Hematopoietic Development in Zebrafish. Dev Dyn. 2003;228(3):323-336.
20. Wang CQ, Krishnan V, Tay LS, et al. Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predis- position due to transcriptional and DNA repair defects. Cell Rep. 2014;8(3):767-782.
21. Bruijn M De, Dzierzak E. Runx transcrip- tion factors in the development and func- tion of the de fi nitive hematopoietic sys- tem. Blood. 2017;129(15):2061-2070.
22. Wang CQ, Motoda L, Satake M, et al. Runx3 deficiency results in myeloprolifera- tive disorder in aged mice. Blood. 2013; 122(4):562-567.
23. Finck R, Zunder ER, Gonzalez VD, et al. Palladium-based mass tag cell barcoding with a doublet-filtering scheme and single- cell deconvolution algorithm. Nat Protoc. 2015;10(2):316-333.
24. Tusi BK, Wolock SL, Weinreb C, et al. Population snapshots predict early haematopoietic and erythroid hierarchies. Nature. 2018;555(7694):54-60.
25. Wahlestedt M, Norddahl GL, Sten G, et al. An epigenetic component of hematopoietic stem cell aging amenable to reprogram- ming into a young state. Blood. 2013; 121(21):4257-4264.
26. Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC. Regulation of Stem Cell Aging by Metabolism and Epigenetics. Cell Metab. 2017;26(3):460-474.
27. Waki T, Tamura G, Sato M, Terashima M, Nishizuka S, Motoyama T. Promoter methylation status of DAP-kinase and RUNX3 genes in neoplastic and non-neo- plastic gastric epithelia. Cancer Sci. 2003;
94(4):360-364.
28. Gunnell A, Webb HM, Wood CD, et al.
RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus tran- scription factors regulates B cell growth. Nucleic Acids Res. 2016;44(10):4636-4650.
29. Mabuchi M, Kataoka H, Miura Y, et al. Tumor suppressor, AT motif binding factor 1 (ATBF1), translocates to the nucleus with runt domain transcription factor 3 (RUNX3) in response to TGF- signal trans- duction. Biochem Biophys Res Commun. 2010;398(2):321-325.
30. Ogawa S, Satake M, Ikuta K. Physical and functional interactions between STAT5 and Runx transcription factors. J Biochem. 2008;143(5):695-709.
31. Torquati A, O’Rear L, Longobardi L, Spagnoli A, Richards WO, Daniel Beauchamp R. RUNX3 inhibits cell prolifer- ation and induces apoptosis by reinstating transforming growth factor beta respon- siveness in esophageal adenocarcinoma cells. Surgery. 2004;136(2):310-316.
32. Chen X, Deng Y, Shi Y, et al. Loss of expres- sion rather than cytoplasmic mislocaliza- tion of RUNX3 predicts worse outcome in non-small cell lung cancer. Oncol Lett. 2018;15(4):5043-5055.
33. Kuvardina ON, Herglotz J, Kolodziej S, et al. RUNX1 represses the erythroid gene expression program during megakaryocytic differentiation. Blood. 2015;125(23):3570- 3579.
34. Bagger FO, Kinalis S, Rapin N. BloodSpot: a database of healthy and malignant haematopoiesis updated with purified and single cell mRNA sequencing profiles. Nucleic Acids Res. 2019;47(D1):D881- D885.
35. Goodnough LT, Schrier SL. Evaluation and Management of Anemia in the Elderly. Am J Hematol. 2014;89(1):88-96.
36. Krishnan V, Ito Y. RUNX3 loss turns on the dark side of TGF-beta signaling. Oncoscience. 2017;4(11-12):156-157.
37. Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during home- ostasis and regeneration. Nat Med. 2014;20(8):833-846.
38. Waki T, Tamura G, Sato M, Motoyama T. Age-related methylation of tumor suppres- sor and tumor-related genes: An analysis of autopsy samples. Oncogene. 2003; 22(26):4128-4133.
39. Li B, Ding L, Yang C, et al. Characterization of transcription factor networks involved in umbilical cord blood CD34+ stem cells- derived erythropoiesis. PLoS One. 2014;9(9):e107133.
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