CoChat
Sign Up
Cited by 189Acute Myeloid Leukemia ResearchHematopoietic Stem Cell TransplantationBlood disorders and treatments

Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS

Open access
Trowbridge, Jennifer J., Starczynowski, Daniel T.·2021·Journal of Experimental Medicine
DOI 10.1084/jem.20201544PMC PMC8210621
Open this paper in CoChat — free accountOpen PDF

Abstract

With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1084/jem.20201544

Cites

18 of 18 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Human MDS HSPCs show significant innate immune system dysregulation and resistance to the pro-proliferative effects of inflammation.

    “Human myelodysplastic syndrome (MDS) HSPCs have shown significant innate immune system dysregulation and resistance to the pro-proliferative effects of inflammation [69,80,81].”

    From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [81]

    The MDS section states that innate immune and inflammatory signaling is dysregulated in human MDS HSPCs. The Preleukemia and MDS section describes a different response to inflammation and a competitive advantage over normal HSPCs, but does not establish resistance to inflammation’s pro-proliferative effects; it suggests that inflammatory conditions may favor MDS HSPC expansion. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Isolated effects of individual inflammatory cytokines, including type 1 interferons (IFNa/b), type 2 IFN (IFNg), TNFa, and IL-1, have been well-documented in mouse hematopoietic development.

    “The isolated effects of individual inflammatory cytokines, including type 1 interferons (IFNa/b) 1-3 , type 2 IFN (IFNg) 4-6 , TNFa 7,8 , and IL-1 9-11 , have been well-documented in mouse hematopoietic development.”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [8]

    The “Inflamm-aging and CHIP” section (page unavailable) reports effects of type I IFN signaling on HSCs in young mice and states that IFN-γ drives expansion of Dnmt3a-knockout HSCs. The “Preleukemia and MDS” section reports that targeting TNF restores HSC function in a mouse model. The copy mentions IL-1β in inflammatory contexts but does not document an isolated effect of IL-1 on mouse hematopoietic development; its examples also focus on HSC function, aging, and premalignancy rather than hematopoietic development generally. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 114

  1. Abegunde, S.O., R. Buckstein, R.A. Wells, and M.J. Rauh. 2018. An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59: 60– 65. 10.1016/j.exphem.2017.11.002 29195897 · DOI · Paper page
  2. Abelson, S., and J.C.Y. Wang. 2018. Age-related clonal hematopoiesis: implications for hematopoietic stem cell transplantation. Curr. Opin. Hematol. 25: 441– 445. 10.1097/MOH.0000000000000465 30124476 · DOI
  3. Adelman, E.R., H.T. Huang, A. Roisman, A. Olsson, A. Colaprico, T. Qin, R.C. Lindsley, R. Bejar, N. Salomonis, H.L. Grimes, and M.E. Figueroa. 2019. Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia. Cancer Discov. 9: 1080– 1101. 10.1158/2159-8290.CD-18-1474 31085557 PMC7080409 · DOI
  4. Akunuru, S., and H. Geiger. 2016. Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells. Trends Mol. Med. 22: 701– 712. 10.1016/j.molmed.2016.06.003 27380967 PMC4969095 · DOI
  5. Ayachi, S., M. Buscarlet, and L. Busque. 2020. 60 Years of clonal hematopoiesis research: From X-chromosome inactivation studies to the identification of driver mutations. Exp. Hematol. 83: 2– 11. 10.1016/j.exphem.2020.01.008 32001340 · DOI
  6. Baldridge, M.T., K.Y. King, N.C. Boles, D.C. Weksberg, and M.A. Goodell. 2010. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 465: 793– 797. 10.1038/nature09135 20535209 PMC2935898 · DOI · Paper page
  7. Balka, K.R., and D. De Nardo. 2019. Understanding early TLR signaling through the Myddosome. J. Leukoc. Biol. 105: 339– 351. 10.1002/JLB.MR0318-096R 30256449 · DOI
  8. Banerjee, T., L.M. Calvi, M.W. Becker, and J.L. Liesveld. 2019. Flaming and fanning: The Spectrum of inflammatory influences in myelodysplastic syndromes. Blood Rev. 36: 57– 69. 10.1016/j.blre.2019.04.004 31036385 PMC6711159 · DOI
  9. Basheer, F., and G. Vassiliou. 2021. Mouse Models of Myeloid Malignancies. Cold Spring Harb. Perspect. Med. 11: a035535. 10.1101/cshperspect.a035535 32071146 PMC7778217 · DOI
  10. Basiorka, A.A., K.L. McGraw, E.A. Eksioglu, X. Chen, J. Johnson, L. Zhang, Q. Zhang, B.A. Irvine, T. Cluzeau, D.A. Sallman,. 2016. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 128: 2960– 2975. 10.1182/blood-2016-07-730556 27737891 PMC5179338 · DOI
  11. Bewersdorf, J.P., and A.M. Zeidan. 2019. Transforming growth factor (TGF)-β pathway as a therapeutic target in lower risk myelodysplastic syndromes. Leukemia. 33: 1303– 1312. 10.1038/s41375-019-0448-2 30962581 · DOI
  12. Bogeska, R., P. Kaschutnig, M. Fawaz, A.-M. Mikecin, M. Buchler-Schaff, S. Paffenholz, N. Asada, F. Frauhammer, F. Buettner, M. Ball,. 2020. Hematopoietic stem cells fail to regenerate following inflammatory challenge. bioRxiv. 10.1101/2020.08.01.230433. (Preprint posted August 3, 2020) · DOI
  13. Boldin, M.P., K.D. Taganov, D.S. Rao, L. Yang, J.L. Zhao, M. Kalwani, Y. Garcia-Flores, M. Luong, A. Devrekanli, J. Xu,. 2011. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J. Exp. Med. 208: 1189– 1201. 10.1084/jem.20101823 21555486 PMC3173243 · DOI · Paper page
  14. Bonnefond, A., B. Skrobek, S. Lobbens, E. Eury, D. Thuillier, S. Cauchi, O. Lantieri, B. Balkau, E. Riboli, M. Marre,. 2013. Association between large detectable clonal mosaicism and type 2 diabetes with vascular complications. Nat. Genet. 45: 1040– 1043. 10.1038/ng.2700 23852171 · DOI · Paper page
  15. Brennan, J.J., and T.D. Gilmore. 2018. Evolutionary Origins of Toll-like Receptor Signaling. Mol. Biol. Evol. 35: 1576– 1587. 10.1093/molbev/msy050 29590394 · DOI
  16. Cai, Z., J.J. Kotzin, B. Ramdas, S. Chen, S. Nelanuthala, L.R. Palam, R. Pandey, R.S. Mali, Y. Liu, M.R. Kelley,. 2018. Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis. Cell Stem Cell. 23: 833– 849.e5. 10.1016/j.stem.2018.10.013 30526882 PMC6317370 · DOI · Paper page
  17. Cazzola, M. 2020. Myelodysplastic Syndromes. N. Engl. J. Med. 383: 1358– 1374. 10.1056/NEJMra1904794 32997910 · DOI
  18. Challen, G.A., N.C. Boles, S.M. Chambers, and M.A. Goodell. 2010. Distinct hematopoietic stem cell subtypes are differentially regulated by TGF-beta1. Cell Stem Cell. 6: 265– 278. 10.1016/j.stem.2010.02.002 20207229 PMC2837284 · DOI
  19. Chambers, S.M., C.A. Shaw, C. Gatza, C.J. Fisk, L.A. Donehower, and M.A. Goodell. 2007. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 5: e201. 10.1371/journal.pbio.0050201 17676974 PMC1925137 · DOI
  20. Chen, J., Y.R. Kao, D. Sun, T.I. Todorova, D. Reynolds, S.R. Narayanagari, C. Montagna, B. Will, A. Verma, and U. Steidl. 2019. Myelodysplastic syndrome progression to acute myeloid leukemia at the stem cell level. Nat. Med. 25: 103– 110. 10.1038/s41591-018-0267-4 30510255 PMC6436966 · DOI
  21. Cimmino, L., I. Dolgalev, Y. Wang, A. Yoshimi, G.H. Martin, J. Wang, V. Ng, B. Xia, M.T. Witkowski, M. Mitchell-Flack,. 2017. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. 170: 1079– 1095.e20. 10.1016/j.cell.2017.07.032 28823558 PMC5755977 · DOI · Paper page
  22. Côme, C., A. Balhuizen, D. Bonnet, and B.T. Porse. 2020. Myelodysplastic syndrome patient-derived xenografts: from no options to many. Haematologica. 105: 864– 869. 10.3324/haematol.2019.233320 32193253 PMC7109759 · DOI
  23. Cook, E.K., T. Izukawa, S. Young, G. Rosen, M. Jamali, L. Zhang, D. Johnson, E. Bain, J. Hilland, C.K. Ferrone,. 2019. Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis. Blood Adv. 3: 2482– 2486. 10.1182/bloodadvances.2018024729 31434682 PMC6712533 · DOI
  24. Corey, S.J., M.D. Minden, D.L. Barber, H. Kantarjian, J.C. Wang, and A.D. Schimmer. 2007. Myelodysplastic syndromes: the complexity of stem-cell diseases. Nat. Rev. Cancer. 7: 118– 129. 10.1038/nrc2047 17251918 · DOI
  25. DeZern, A.E., L. Malcovati, and B.L. Ebert. 2019. CHIP, CCUS, and Other Acronyms: Definition, Implications, and Impact on Practice. Am. Soc. Clin. Oncol. Educ. Book. 39: 400– 410. 10.1200/EDBK_239083 31099654 · DOI
  26. Dorsheimer, L., B. Assmus, T. Rasper, C.A. Ortmann, A. Ecke, K. Abou-El-Ardat, T. Schmid, B. Brüne, S. Wagner, H. Serve,. 2019. Association of Mutations Contributing to Clonal Hematopoiesis With Prognosis in Chronic Ischemic Heart Failure. JAMA Cardiol. 4: 25– 33. 10.1001/jamacardio.2018.3965 30566180 PMC6439691 · DOI · Paper page
  27. Dorshkind, K., E. Montecino-Rodriguez, and R.A. Signer. 2009. The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 9: 57– 62. 10.1038/nri2471 19104499 · DOI
  28. Esplin, B.L., T. Shimazu, R.S. Welner, K.P. Garrett, L. Nie, Q. Zhang, M.B. Humphrey, Q. Yang, L.A. Borghesi, and P.W. Kincade. 2011. Chronic exposure to a TLR ligand injures hematopoietic stem cells. J. Immunol. 186: 5367– 5375. 10.4049/jimmunol.1003438 21441445 PMC3086167 · DOI
  29. Evavold, C.L., J. Ruan, Y. Tan, S. Xia, H. Wu, and J.C. Kagan. 2018. The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity. 48: 35– 44.e6. 10.1016/j.immuni.2017.11.013 29195811 PMC5773350 · DOI · Paper page
  30. Fang, J., B. Barker, L. Bolanos, X. Liu, A. Jerez, H. Makishima, S. Christie, X. Chen, D.S. Rao, H.L. Grimes,. 2014. Myeloid malignancies with chromosome 5q deletions acquire a dependency on an intrachromosomal NF-κB gene network. Cell Rep. 8: 1328– 1338. 10.1016/j.celrep.2014.07.062 25199827 PMC4237069 · DOI
  31. Fang, J., L.C. Bolanos, K. Choi, X. Liu, S. Christie, S. Akunuru, R. Kumar, D. Wang, X. Chen, K.D. Greis,. 2017. Ubiquitination of hnRNPA1 by TRAF6 links chronic innate immune signaling with myelodysplasia. Nat. Immunol. 18: 236– 245. 10.1038/ni.3654 28024152 PMC5423405 · DOI
  32. Fenaux, P., U. Platzbecker, G.J. Mufti, G. Garcia-Manero, R. Buckstein, V. Santini, M. Díez-Campelo, C. Finelli, M. Cazzola, O. Ilhan,. 2020. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N. Engl. J. Med. 382: 140– 151. 10.1056/NEJMoa1908892 31914241 · DOI
  33. Fernandes-Alnemri, T., S. Kang, C. Anderson, J. Sagara, K.A. Fitzgerald, and E.S. Alnemri. 2013. Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome. J. Immunol. 191: 3995– 3999. 10.4049/jimmunol.1301681 24043892 PMC3924784 · DOI
  34. Fuster, J.J., S. MacLauchlan, M.A. Zuriaga, M.N. Polackal, A.C. Ostriker, R. Chakraborty, C.L. Wu, S. Sano, S. Muralidharan, C. Rius,. 2017. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 355: 842– 847. 10.1126/science.aag1381 28104796 PMC5542057 · DOI · Paper page
  35. Fuster, J.J., M.A. Zuriaga, V. Zorita, S. MacLauchlan, M.N. Polackal, V. Viana-Huete, A. Ferrer-Pérez, N. Matesanz, A. Herrero-Cervera, S. Sano,. 2020. TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity. Cell Rep. 33: 108326. 10.1016/j.celrep.2020.108326 33113366 PMC7856871 · DOI · Paper page
  36. Gañán-Gómez, I., Y. Wei, D.T. Starczynowski, S. Colla, H. Yang, M. Cabrero-Calvo, Z.S. Bohannan, A. Verma, U. Steidl, and G. Garcia-Manero. 2015. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 29: 1458– 1469. 10.1038/leu.2015.69 25761935 PMC4857136 · DOI · Paper page
  37. Gao, T., R. Ptashkin, K.L. Bolton, M. Sirenko, C. Fong, B. Spitzer, K. Menghrajani, J.E.A. Ossa, Y. Zhou, E. Bernard,. 2021. Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis. Nat. Commun. 12: 338. 10.1038/s41467-020-20565-7 33436578 PMC7804935 · DOI
  38. Genovese, G., A.K. Kähler, R.E. Handsaker, J. Lindberg, S.A. Rose, S.F. Bakhoum, K. Chambert, E. Mick, B.M. Neale, M. Fromer,. 2014. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371: 2477– 2487. 10.1056/NEJMoa1409405 25426838 PMC4290021 · DOI · Paper page
  39. Grants, J.M., J. Wegrzyn, T. Hui, K. O’Neill, M. Shadbolt, D.J.H.F. Knapp, J. Parker, Y. Deng, A. Gopal, T.R. Docking,. 2020. Altered microRNA expression links IL6 and TNF-induced inflammaging with myeloid malignancy in humans and mice. Blood. 135: 2235– 2251. 10.1182/blood.2019003105 32384151 · DOI
  40. Greenberg, P.L., H. Tuechler, J. Schanz, G. Sanz, G. Garcia-Manero, F. Solé, J.M. Bennett, D. Bowen, P. Fenaux, F. Dreyfus,. 2012. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 120: 2454– 2465. 10.1182/blood-2012-03-420489 22740453 PMC4425443 · DOI
  41. Hormaechea-Agulla, D., D.T. Le, and K.Y. King. 2020. Common Sources of Inflammation and Their Impact on Hematopoietic Stem Cell Biology. Curr. Stem Cell Rep. 6: 96– 107. 10.1007/s40778-020-00177-z PMC7429415 32837857 · DOI
  42. Ivy, K.S., and P. Brent Ferrell Jr. 2018. Disordered Immune Regulation and its Therapeutic Targeting in Myelodysplastic Syndromes. Curr. Hematol. Malig. Rep. 13: 244– 255. 10.1007/s11899-018-0463-9 29934935 PMC6560359 · DOI
  43. Jaiswal, S., P. Natarajan, A.J. Silver, C.J. Gibson, A.G. Bick, E. Shvartz, M. McConkey, N. Gupta, S. Gabriel, D. Ardissino,. 2017. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N. Engl. J. Med. 377: 111– 121. 10.1056/NEJMoa1701719 28636844 PMC6717509 · DOI · Paper page
  44. Kaczmarek, A., P. Vandenabeele, and D.V. Krysko. 2013. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 38: 209– 223. 10.1016/j.immuni.2013.02.003 23438821 · DOI · Paper page
  45. Kagan, J.C., V.G. Magupalli, and H. Wu. 2014. SMOCs: supramolecular organizing centres that control innate immunity. Nat. Rev. Immunol. 14: 821– 826. 10.1038/nri3757 25359439 PMC4373346 · DOI
  46. Kawasaki, T., and T. Kawai. 2014. Toll-like receptor signaling pathways. Front. Immunol. 5: 461. 10.3389/fimmu.2014.00461 25309543 PMC4174766 · DOI
  47. King, K.Y., and M.A. Goodell. 2011. Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat. Rev. Immunol. 11: 685– 692. 10.1038/nri3062 21904387 PMC4154310 · DOI
  48. Kumar, M.S., A. Narla, A. Nonami, A. Mullally, N. Dimitrova, B. Ball, J.R. McAuley, L. Poveromo, J.L. Kutok, N. Galili,. 2011. Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome. Blood. 118: 4666– 4673. 10.1182/blood-2010-12-324715 21873545 PMC3208282 · DOI
  49. Kwok, B., J.M. Hall, J.S. Witte, Y. Xu, P. Reddy, K. Lin, R. Flamholz, B. Dabbas, A. Yung, J. Al-Hafidh,. 2015. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood. 126: 2355– 2361. 10.1182/blood-2015-08-667063 26429975 PMC4653764 · DOI
  50. Lam, J., M. van den Bosch, J. Wegrzyn, J. Parker, R. Ibrahim, K. Slowski, L. Chang, S. Martinez-Høyer, G. Condorelli, M. Boldin,. 2018. miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ signaling. Nat. Commun. 9: 2418. 10.1038/s41467-018-04831-3 29925839 PMC6010451 · DOI
  51. Lee, S.C., K. North, E. Kim, E. Jang, E. Obeng, S.X. Lu, B. Liu, D. Inoue, A. Yoshimi, M. Ki,. 2018. Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations. Cancer Cell. 34: 225– 241.e8. 10.1016/j.ccell.2018.07.003 30107174 PMC6373472 · DOI · Paper page
  52. Li, S., A. Strelow, E.J. Fontana, and H. Wesche. 2002. IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc. Natl. Acad. Sci. USA. 99: 5567– 5572. 10.1073/pnas.082100399 11960013 PMC122810 · DOI
  53. Li, X., Q. Zhang, Y. Ding, Y. Liu, D. Zhao, K. Zhao, Q. Shen, X. Liu, X. Zhu, N. Li,. 2016. Erratum: Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat. Immunol. 17: 1005. 10.1038/ni0816-1005d 27434014 · DOI
  54. Liu, X., Z. Zhang, J. Ruan, Y. Pan, V.G. Magupalli, H. Wu, and J. Lieberman. 2016. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 535: 153– 158. 10.1038/nature18629 27383986 PMC5539988 · DOI · Paper page
  55. Lu, L.F., M.P. Boldin, A. Chaudhry, L.L. Lin, K.D. Taganov, T. Hanada, A. Yoshimura, D. Baltimore, and A.Y. Rudensky. 2010. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 142: 914– 929. 10.1016/j.cell.2010.08.012 20850013 PMC3049116 · DOI
  56. Luo, H., W.C. Mu, R. Karki, H.H. Chiang, M. Mohrin, J.J. Shin, R. Ohkubo, K. Ito, T.D. Kanneganti, and D. Chen. 2019. Mitochondrial Stress-Initiated Aberrant Activation of the NLRP3 Inflammasome Regulates the Functional Deterioration of Hematopoietic Stem Cell Aging. Cell Rep. 26: 945– 954.e4. 10.1016/j.celrep.2018.12.101 30673616 PMC6371804 · DOI · Paper page
  57. Maratheftis, C.I., E. Andreakos, H.M. Moutsopoulos, and M. Voulgarelis. 2007. Toll-like receptor-4 is up-regulated in hematopoietic progenitor cells and contributes to increased apoptosis in myelodysplastic syndromes. Clin. Cancer Res. 13: 1154– 1160. 10.1158/1078-0432.CCR-06-2108 17317824 · DOI
  58. Matatall, K.A., M. Jeong, S. Chen, D. Sun, F. Chen, Q. Mo, M. Kimmel, and K.Y. King. 2016. Chronic Infection Depletes Hematopoietic Stem Cells through Stress-Induced Terminal Differentiation. Cell Rep. 17: 2584– 2595. 10.1016/j.celrep.2016.11.031 27926863 PMC5161248 · DOI · Paper page
  59. Mei, Y., B. Zhao, A.A. Basiorka, J. Yang, L. Cao, J. Zhang, A. List, and P. Ji. 2018. Age-related inflammatory bone marrow microenvironment induces ineffective erythropoiesis mimicking del(5q) MDS. Leukemia. 32: 1023– 1033. 10.1038/leu.2017.326 29263441 PMC5886057 · DOI
  60. Meisel, M., R. Hinterleitner, A. Pacis, L. Chen, Z.M. Earley, T. Mayassi, J.F. Pierre, J.D. Ernest, H.J. Galipeau, N. Thuille,. 2018. Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature. 557: 580– 584. 10.1038/s41586-018-0125-z 29769727 PMC6238954 · DOI · Paper page
  61. Monlish, D.A., S.T. Bhatt, and L.G. Schuettpelz. 2016. The Role of Toll-Like Receptors in Hematopoietic Malignancies. Front. Immunol. 7: 390. 10.3389/fimmu.2016.00390 27733853 PMC5039188 · DOI
  62. Monlish, D.A., S.T. Bhatt, E.J. Duncavage, Z.J. Greenberg, J.L. Keller, M.P. Romine, W. Yang, P.D. Aplan, M.J. Walter, and L.G. Schuettpelz. 2018. Loss of Toll-like receptor 2 results in accelerated leukemogenesis in the NUP98-HOXD13 mouse model of MDS. Blood. 131: 1032– 1035. 10.1182/blood-2017-08-801944 29358180 PMC5833264 · DOI
  63. Monlish, D.A., Z.J. Greenberg, S.T. Bhatt, K.M. Leonard, M.P. Romine, Q. Dong, L. Bendesky, E.J. Duncavage, J.A. Magee, and L.G. Schuettpelz. 2020. TLR2/6 signaling promotes the expansion of premalignant hematopoietic stem and progenitor cells in the NUP98-HOXD13 mouse model of MDS. Exp. Hematol. 88: 42– 55. 10.1016/j.exphem.2020.07.001 32652111 PMC7673652 · DOI
  64. Mossadegh-Keller, N., S. Sarrazin, P.K. Kandalla, L. Espinosa, E.R. Stanley, S.L. Nutt, J. Moore, and M.H. Sieweke. 2013. M-CSF instructs myeloid lineage fate in single haematopoietic stem cells. Nature. 497: 239– 243. 10.1038/nature12026 23575636 PMC3679883 · DOI
  65. Muench, D.E., K. Ferchen, C.S. Velu, K. Pradhan, K. Chetal, X. Chen, M.T. Weirauch, C. Colmenares, A. Verma, N. Salomonis, and H.L. Grimes. 2018. SKI controls MDS-associated chronic TGF-β signaling, aberrant splicing, and stem cell fitness. Blood. 132: e24– e34. 10.1182/blood-2018-06-860890 30249787 PMC6251005 · DOI
  66. Nagai, Y., K.P. Garrett, S. Ohta, U. Bahrun, T. Kouro, S. Akira, K. Takatsu, and P.W. Kincade. 2006. Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. Immunity. 24: 801– 812. 10.1016/j.immuni.2006.04.008 16782035 PMC1626529 · DOI
  67. Niederkorn, M., K. Hueneman, K. Choi, M.E. Varney, L. Romano, M.A. Pujato, K.D. Greis, J.I. Inoue, R. Meetei, and D.T. Starczynowski. 2020. TIFAB Regulates USP15-Mediated p53 Signaling during Stressed and Malignant Hematopoiesis. Cell Rep. 30: 2776– 2790.e6. 10.1016/j.celrep.2020.01.093 32101751 PMC7384867 · DOI
  68. Nilsson, L., I. Astrand-Grundström, I. Arvidsson, B. Jacobsson, E. Hellström-Lindberg, R. Hast, and S.E. Jacobsen. 2000. Isolation and characterization of hematopoietic progenitor/stem cells in 5q-deleted myelodysplastic syndromes: evidence for involvement at the hematopoietic stem cell level. Blood. 96: 2012– 2021. 10.1182/blood.V96.6.2012 10979941 · DOI
  69. Nilsson, L., P. Edén, E. Olsson, R. Månsson, I. Astrand-Grundström, B. Strömbeck, K. Theilgaard-Mönch, K. Anderson, R. Hast, E. Hellström-Lindberg,. 2007. The molecular signature of MDS stem cells supports a stem-cell origin of 5q myelodysplastic syndromes. Blood. 110: 3005– 3014. 10.1182/blood-2007-03-079368 17616640 · DOI
  70. Nimer, S.D. 2008. Myelodysplastic syndromes. Blood. 111: 4841– 4851. 10.1182/blood-2007-08-078139 18467609 · DOI
  71. Ogawa, S. 2019. Genetics of MDS. Blood. 133: 1049– 1059. 10.1182/blood-2018-10-844621 30670442 PMC6587668 · DOI
  72. Ombrato, L., E. Nolan, I. Kurelac, A. Mavousian, V.L. Bridgeman, I. Heinze, P. Chakravarty, S. Horswell, E. Gonzalez-Gualda, G. Matacchione,. 2019. Author Correction: Metastatic-niche labelling reveals parenchymal cells with stem features. Nature. 575: E8. 10.1038/s41586-019-1697-y 31719688 · DOI
  73. Pang, W.W., J.V. Pluvinage, E.A. Price, K. Sridhar, D.A. Arber, P.L. Greenberg, S.L. Schrier, C.Y. Park, and I.L. Weissman. 2013. Hematopoietic stem cell and progenitor cell mechanisms in myelodysplastic syndromes. Proc. Natl. Acad. Sci. USA. 110: 3011– 3016. 10.1073/pnas.1222861110 23388639 PMC3581956 · DOI · Paper page
  74. Paracatu, L.C., and L.G. Schuettpelz. 2020. Contribution of Aberrant Toll Like Receptor Signaling to the Pathogenesis of Myelodysplastic Syndromes. Front. Immunol. 11: 1236. 10.3389/fimmu.2020.01236 32625214 PMC7313547 · DOI
  75. Pellagatti, A., M. Cazzola, A. Giagounidis, J. Perry, L. Malcovati, M.G. Della Porta, M. Jädersten, S. Killick, A. Verma, C.J. Norbury,. 2010. Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells. Leukemia. 24: 756– 764. 10.1038/leu.2010.31 20220779 · DOI
  76. Qiao, Q., and H. Wu. 2015. Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation. Sci. China Life Sci. 58: 1067– 1072. 10.1007/s11427-015-4951-z 26511517 PMC4847730 · DOI
  77. Rea, I.M., D.S. Gibson, V. McGilligan, S.E. McNerlan, H.D. Alexander, and O.A. Ross. 2018. Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front. Immunol. 9: 586. 10.3389/fimmu.2018.00586 29686666 PMC5900450 · DOI · Paper page
  78. Rhyasen, G.W., L. Bolanos, J. Fang, A. Jerez, M. Wunderlich, C. Rigolino, L. Mathews, M. Ferrer, N. Southall, R. Guha,. 2013. Targeting IRAK1 as a therapeutic approach for myelodysplastic syndrome. Cancer Cell. 24: 90– 104. 10.1016/j.ccr.2013.05.006 23845443 PMC3711103 · DOI · Paper page
  79. Ribezzo, F., I.A.M. Snoeren, S. Ziegler, J. Stoelben, P.A. Olofsen, A. Henic, M.V. Ferreira, S. Chen, U.S.A. Stalmann, G. Buesche,. 2019. Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome. Leukemia. 33: 1759– 1772. 10.1038/s41375-018-0350-3 30651631 · DOI · Paper page
  80. Rubin, J.R., H.C. Pitluk, T.A. King, M. Hutton, E.F. Kieger, F.R. Plecha, and N.R. Hertzer. 1988. Carotid endarterectomy in a metropolitan community: the early results after 8535 operations. J. Vasc. Surg. 7: 256– 260. 10.1016/0741-5214(88)90144-9 3339771 · DOI
  81. Sallman, D.A., T. Cluzeau, A.A. Basiorka, and A. List. 2016. Unraveling the Pathogenesis of MDS: The NLRP3 Inflammasome and Pyroptosis Drive the MDS Phenotype. Front. Oncol. 6: 151. 10.3389/fonc.2016.00151 27379212 PMC4909736 · DOI
  82. SanMiguel, J.M., K. Young, and J.J. Trowbridge. 2020. Hand in hand: intrinsic and extrinsic drivers of aging and clonal hematopoiesis. Exp. Hematol. 91: 1– 9. 10.1016/j.exphem.2020.09.197 32991978 PMC7736302 · DOI
  83. Sano, S., K. Oshima, Y. Wang, S. MacLauchlan, Y. Katanasaka, M. Sano, M.A. Zuriaga, M. Yoshiyama, D. Goukassian, M.A. Cooper,. 2018. Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome. J. Am. Coll. Cardiol. 71: 875– 886. 10.1016/j.jacc.2017.12.037 29471939 PMC5828038 · DOI · Paper page
  84. Schneider, R.K., M. Schenone, M.V. Ferreira, R. Kramann, C.E. Joyce, C. Hartigan, F. Beier, T.H. Brümmendorf, U. Germing, U. Platzbecker,. 2016. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat. Med. 22: 288– 297. 10.1038/nm.4047 26878232 PMC4870050 · DOI
  85. Shastri, A., B. Will, U. Steidl, and A. Verma. 2017. Stem and progenitor cell alterations in myelodysplastic syndromes. Blood. 129: 1586– 1594. 10.1182/blood-2016-10-696062 28159737 PMC5364336 · DOI
  86. Smith, M.A., G.S. Choudhary, A. Pellagatti, K. Choi, L.C. Bolanos, T.D. Bhagat, S. Gordon-Mitchell, D. Von Ahrens, K. Pradhan, V. Steeples,. 2019. U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies. Nat. Cell Biol. 21: 640– 650. 10.1038/s41556-019-0314-5 31011167 PMC6679973 · DOI
  87. Smith, M.A., A.E. Culver-Cochran, E.R. Adelman, G.W. Rhyasen, A. Ma, M.E. Figueroa, and D.T. Starczynowski. 2020. TNFAIP3 Plays a Role in Aging of the Hematopoietic System. Front. Immunol. 11: 536442. 10.3389/fimmu.2020.536442 33224133 PMC7670064 · DOI
  88. Stahl, M., M. DeVeaux, T. de Witte, J. Neukirchen, M.A. Sekeres, A.M. Brunner, G.J. Roboz, D.P. Steensma, V.R. Bhatt, U. Platzbecker,. 2018. The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort. Blood Adv. 2: 1765– 1772. 10.1182/bloodadvances.2018019414 30037803 PMC6058241 · DOI
  89. Starczynowski, D.T., and A. Karsan. 2010. Innate immune signaling in the myelodysplastic syndromes. Hematol. Oncol. Clin. North Am. 24: 343– 359. 10.1016/j.hoc.2010.02.008 20359630 · DOI
  90. Starczynowski, D.T., F. Kuchenbauer, B. Argiropoulos, S. Sung, R. Morin, A. Muranyi, M. Hirst, D. Hogge, M. Marra, R.A. Wells,. 2010. Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat. Med. 16: 49– 58. 10.1038/nm.2054 19898489 · DOI
  91. Stoner, S.A., M. Yan, K.T.H. Liu, K.I. Arimoto, T. Shima, H.Y. Wang, D.T. Johnson, R. Bejar, C. Jamieson, K.L. Guan, and D.E. Zhang. 2019. Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation. Blood. 134: 1730– 1744. 10.1182/blood.2019000170 31434702 PMC6856986 · DOI
  92. Su, Y.L., X. Wang, M. Mann, T.P. Adamus, D. Wang, D.F. Moreira, Z. Zhang, C. Ouyang, X. He, B. Zhang,. 2020. Myeloid cell-targeted miR-146a mimic inhibits NF-κB-driven inflammation and leukemia progression in vivo. Blood. 135: 167– 180. 10.1182/blood.2019002045 31805184 PMC6966933 · DOI
  93. Sun, D., M. Luo, M. Jeong, B. Rodriguez, Z. Xia, R. Hannah, H. Wang, T. Le, K.F. Faull, R. Chen,. 2014. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 14: 673– 688. 10.1016/j.stem.2014.03.002 24792119 PMC4070311 · DOI · Paper page
  94. Takizawa, H., K. Fritsch, L.V. Kovtonyuk, Y. Saito, C. Yakkala, K. Jacobs, A.K. Ahuja, M. Lopes, A. Hausmann, W.D. Hardt,. 2017. Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness. Cell Stem Cell. 21: 225– 240.e5. 10.1016/j.stem.2017.06.013 28736216 · DOI
  95. Tecalco-Cruz, A.C., D.G. Ríos-López, G. Vázquez-Victorio, R.E. Rosales-Alvarez, and M. Macías-Silva. 2018. Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease. Signal Transduct. Target. Ther. 3: 15. 10.1038/s41392-018-0015-8 29892481 PMC5992185 · DOI
  96. Vaidya, A., and V.P. Kale. 2015. TGF-β signaling and its role in the regulation of hematopoietic stem cells. Syst. Synth. Biol. 9: 1– 10. 10.1007/s11693-015-9161-2 PMC4427577 25972984 · DOI
  97. Valletta, S., A. Thomas, Y. Meng, X. Ren, R. Drissen, H. Sengül, C. Di Genua, and C. Nerlov. 2020. Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing. Nat. Commun. 11: 4075. 10.1038/s41467-020-17942-7 32796847 PMC7427787 · DOI · Paper page
  98. Van Egeren, D., J. Escabi, M. Nguyen, S. Liu, C.R. Reilly, S. Patel, B. Kamaz, M. Kalyva, D.J. DeAngelo, I. Galinsky,. 2021. Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in myeloproliferative neoplasms. Cell Stem Cell. 28: 514– 523.e9. 10.1016/j.stem.2021.02.001 33621486 PMC7939520 · DOI · Paper page
  99. Varney, M.E., K. Melgar, M. Niederkorn, M. Smith, L. Barreyro, and D.T. Starczynowski. 2015 a. Deconstructing innate immune signaling in myelodysplastic syndromes. Exp. Hematol. 43: 587– 598. 10.1016/j.exphem.2015.05.016 26143580 PMC4635673 · DOI
  100. Varney, M.E., M. Niederkorn, H. Konno, T. Matsumura, J. Gohda, N. Yoshida, T. Akiyama, S. Christie, J. Fang, D. Miller,. 2015 b. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling. J. Exp. Med. 212: 1967– 1985. 10.1084/jem.20141898 26458771 PMC4612089 · DOI
  101. Varney, M.E., K. Choi, L. Bolanos, S. Christie, J. Fang, H.L. Grimes, J.P. Maciejewski, J.I. Inoue, and D.T. Starczynowski. 2017. Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome. Leukemia. 31: 491– 495. 10.1038/leu.2016.276 27733775 PMC5729588 · DOI
  102. Wagner, P.N., Q. Shi, C.T. Salisbury-Ruf, J. Zou, M.R. Savona, Y. Fedoriw, and S.S. Zinkel. 2019. Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice. Blood. 133: 107– 120. 10.1182/blood-2018-05-847335 30413413 PMC6328629 · DOI
  103. Wang, T., A.R. Pine, A.G. Kotini, H. Yuan, L. Zamparo, D.T. Starczynowski, C. Leslie, and E.P. Papapetrou. 2021. Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets. Cell Stem Cell. 28: P1074- 1089.E7. 10.1016/j.stem.2021.01.011 PMC8178190 33571445 · DOI
  104. Wei, Y., S. Dimicoli, C. Bueso-Ramos, R. Chen, H. Yang, D. Neuberg, S. Pierce, Y. Jia, H. Zheng, H. Wang,. 2013. Toll-like receptor alterations in myelodysplastic syndrome. Leukemia. 27: 1832– 1840. 10.1038/leu.2013.180 23765228 PMC4011663 · DOI
  105. Wei, Y., H. Zheng, N. Bao, S. Jiang, C.E. Bueso-Ramos, J. Khoury, C. Class, Y. Lu, K. Lin, H. Yang,. 2018. KDM6B overexpression activates innate immune signaling and impairs hematopoiesis in mice. Blood Adv. 2: 2491– 2504. 10.1182/bloodadvances.2018024166 30275007 PMC6177657 · DOI
  106. Williams, N., J. Lee, L. Moore, E.J. Baxter, J. Hewinson, K.J. Dawson, A. Menzies, A.L. Godfrey, A.R. Green, P.J. Campbell, and J. Nangalia. 2020. Phylogenetic reconstruction of myeloproliferative neoplasm reveals very early origins and lifelong evolution. bioRxiv. 10.1101/2020.11.09.374710 (Posted November 9, 2020). · DOI
  107. Winter, S., S. Shoaie, S. Kordasti, and U. Platzbecker. 2020. Integrating the “Immunome” in the Stratification of Myelodysplastic Syndromes and Future Clinical Trial Design. J. Clin. Oncol. 38: 1723– 1735. 10.1200/JCO.19.01823 32058844 · DOI
  108. Young, A.L., R.S. Tong, B.M. Birmann, and T.E. Druley. 2019. Clonal hematopoiesis and risk of acute myeloid leukemia. Haematologica. 104: 2410– 2417. 10.3324/haematol.2018.215269 31004019 PMC6959179 · DOI
  109. Zeng, Q., J. Shu, Q. Hu, S.H. Zhou, Y.M. Qian, M.H. Hu, L.Y. Hu, Y.G. Wang, Y.M. Zhou, and J.H. Lu. 2016. Apoptosis in human myelodysplastic syndrome CD34+ cells is modulated by the upregulation of TLRs and histone H4 acetylation via a β-arrestin 1 dependent mechanism. Exp. Cell Res. 340: 22– 31. 10.1016/j.yexcr.2015.12.008 26708616 · DOI
  110. Zhang, T.Y., R. Dutta, B. Benard, F. Zhao, R. Yin, and R. Majeti. 2020. IL-6 blockade reverses bone marrow failure induced by human acute myeloid leukemia. Sci. Transl. Med. 12: eaax5104. 10.1126/scitranslmed.aax5104 32269167 PMC7266679 · DOI
  111. Zhao, J.L., D.S. Rao, M.P. Boldin, K.D. Taganov, R.M. O’Connell, and D. Baltimore. 2011. NF-κB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc. Natl. Acad. Sci. USA. 108: 9184– 9189. 10.1073/pnas.1105398108 21576471 PMC3107319 · DOI · Paper page
  112. Zhou, L., C. McMahon, T. Bhagat, C. Alencar, Y. Yu, M. Fazzari, D. Sohal, C. Heuck, K. Gundabolu, C. Ng,. 2011. Reduced SMAD7 leads to overactivation of TGF-beta signaling in MDS that can be reversed by a specific inhibitor of TGF-beta receptor I kinase. Cancer Res. 71: 955– 963. 10.1158/0008-5472.CAN-10-2933 21189329 PMC3032816 · DOI
  113. Zhou, T., M.C. Kinney, L.M. Scott, S.S. Zinkel, and V.I. Rebel. 2015. Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research. Blood. 126: 1057– 1068. 10.1182/blood-2015-01-624239 26077396 PMC4551359 · DOI
  114. Zink, F., S.N. Stacey, G.L. Norddahl, M.L. Frigge, O.T. Magnusson, I. Jonsdottir, T.E. Thorgeirsson, A. Sigurdsson, S.A. Gudjonsson, J. Gudmundsson,. 2017. Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly. Blood. 130: 742– 752. 10.1182/blood-2017-02-769869 28483762 PMC5553576 · DOI · Paper page

Cited by

Sorted by citations

Authors
Trowbridge, J. J., & Starczynowski, D. T.
Affiliations
  • Jackson Laboratory (US)
  • Cincinnati Children's Hospital Medical Center (US)
Corresponding author
  • Trowbridge, Jennifer J.
  • Starczynowski, Daniel T.
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2021-06-15
Volume
218
Issue
7
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20201544
PMC
PMC8210621
OpenAlex
W3171826908
Cited by
189
References
18
Citations by year
2026: 20 · 2025: 37 · 2024: 41 · 2023: 43 · 2022: 40 · 2021: 7
FWCI
5.72
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • National Institute on Aging (R01AG069010, U01AG077925)
  • National Heart, Lung, and Blood Institute (R35HL135787)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113639, R01DK118072, U54DK126108)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
hematopoietic aging, clonal hematopoiesis, myelodysplastic syndrome, innate immunity, inflammation, systemic inflammation, preleukemic clones, clonal dominance, hematopoietic defects, inflammatory signaling, treatment options
MeSH terms
Clonal Hematopoiesis, Aging, Animals, Hematopoiesis, Hematopoietic Stem Cells, Humans, Immunity, Innate, Inflammation, Myelodysplastic Syndromes, Signal Transduction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review