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Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche – Leukemia

  • Dawoud AAZ, Tapper WJ, Cross NCP. Clonal myelopoiesis in the UK Biobank cohort: ASXL1 mutations are strongly associated with smoking. Leukemia. 2020;34:2660–72.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • De-Morgan A, Meggendorfer M, Haferlach C, Shlush L. Male predominance in AML is associated with specific preleukemic mutations. Leukemia. 2021;35:867–70.

    Article 
    PubMed 

    Google Scholar
     

  • Kar SP, Quiros PM, Gu M, Jiang T, Mitchell J, Langdon R, et al. Genome-wide analyses of 200,453 individuals yield new insights into the causes and consequences of clonal hematopoiesis. Nat Genet. 2022;54:1155–66.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bick AG, Weinstock JS, Nandakumar SK, Fulco CP, Bao EL, Zekavat SM, et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature. 2020;586:763–8.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9–16.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. N Engl J Med. 2014;371:2488–98.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. N Engl J Med. 2014;371:2477–87.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cargo CA, Rowbotham N, Evans PA, Barrans SL, Bowen DT, Crouch S, et al. Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression. Blood. 2015;126:2362–5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Abelson S, Collord G, Ng SWK, Weissbrod O, Mendelson Cohen N, Niemeyer E, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature. 2018;559:400–4.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Desai P, Mencia-Trinchant N, Savenkov O, Simon MS, Cheang G, Lee S, et al. Somatic mutations precede acute myeloid leukemia years before diagnosis. Nat Med. 2018;24:1015–23.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Takahashi K, Wang F, Kantarjian H, Doss D, Khanna K, Thompson E, et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 2017;18:100–11.

    Article 
    PubMed 

    Google Scholar
     

  • Coombs CC, Zehir A, Devlin SM, Kishtagari A, Syed A, Jonsson P, et al. Therapy-Related Clonal Hematopoiesis in Patients with Non-hematologic Cancers Is Common and Associated with Adverse Clinical Outcomes. Cell Stem Cell. 2017;21:374–382.e4.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017;377:111–21.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim PG, Niroula A, Shkolnik V, McConkey M, Lin A, Słabicki M, et al. Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis. J Exp Med. 2021;218:e20211872.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Agrawal M, Niroula A, Cunin P, McConkey M, Shkolnik V, Kim PG, et al. TET2-mutant clonal hematopoiesis and risk of gout. Blood. 2022;140:1094–103.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wong WJ, Emdin C, Bick AG, Zekavat SM, Niroula A, Pirruccello JP, et al. Clonal haematopoiesis and risk of chronic liver disease. Nature. 2023;616:747–54.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hecker JS, Hartmann L, Rivière J, Buck MC, van der Garde M, Rothenberg-Thurley M, et al. CHIP and hips: clonal hematopoiesis is common in patients undergoing hip arthroplasty and is associated with autoimmune disease. Blood. 2021;138:1727–32.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ayachi S, Buscarlet M, Busque L. 60 Years of clonal hematopoiesis research: From X-chromosome inactivation studies to the identification of driver mutations. Exp Hematol. 2020;83:2–11.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bouzid H, Belk JA, Jan M, Qi Y, Sarnowski C, Wirth S, et al. Clonal hematopoiesis is associated with protection from Alzheimer’s disease. Nat Med. 2023;29:1662–70.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36:1703–19.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hartmann L, Hecker JS, Rothenberg-Thurley M, Rivière J, Jentzsch M, Ksienzyk B, et al. Compartment-specific mutational landscape of clonal hematopoiesis. Leukemia. 2022;36:2647–55.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Niroula A, Sekar A, Murakami MA, Trinder M, Agrawal M, Wong WJ, et al. Distinction of lymphoid and myeloid clonal hematopoiesis. Nat Med. 2021;27:1921–7.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mitchell E, Spencer Chapman M, Williams N, Dawson KJ, Mende N, Calderbank EF, et al. Clonal dynamics of haematopoiesis across the human lifespan. Nature. 2022;606:343–50.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fabre MA, de Almeida JG, Fiorillo E, Mitchell E, Damaskou A, Rak J, et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature. 2022;606:335–42.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baldow C, Thielecke L, Glauche I. Model based analysis of clonal developments allows for early detection of monoclonal conversion and leukemia. PLoS One. 2016;11:e0165129.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vedi A, Hayler D, Biezuner T, Santoro A, Sham K, Tuval A, et al. DNMT3A R882 Mutation in Human Haematopoietic Stem Cells Alters Differentiation Towards Neutrophils and Monocytes. Blood. 2021;138:2162.

    Article 

    Google Scholar
     

  • Nam AS, Dusaj N, Izzo F, Murali R, Myers RM, Mouhieddine TH, et al. Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation. Nat Genet. 2022;54:1514.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huerga Encabo H, Aramburu IV, Garcia-Albornoz M, Piganeau M, Wood H, Song A, et al. Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils. Cell Stem Cell. 2023;30:781–799.e9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Arends CM, Galan-Sousa J, Hoyer K, Chan W, Jäger M, Yoshida K, et al. Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. Leukemia. 2018;32:1908–19.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buscarlet M, Provost S, Zada YF, Bourgoin V, Mollica L, Dubé MP, et al. Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A. Blood. 2018;132:277–80.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Abplanalp WT, Schuhmacher B, Cremer S, Merten M, Shumliakivska M, Macinkovic I, et al. Cell-intrinsic effects of clonal hematopoiesis in heart failure. Nat Cardiovasc Res. 2023;2:819–34.


    Google Scholar
     

  • Watson CJ, Papula AL, Poon GYP, Wong WH, Young AL, Druley TE, et al. The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science. 2020;367:1449–54.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Robertson NA, Latorre-Crespo E, Terradas-Terradas M, Lemos-Portela J, Purcell AC, Livesey BJ, et al. Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects. Nat Med. 2022;28:1439–46.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Williams N, Lee J, Mitchell E, Moore L, Baxter EJ, Hewinson J, et al. Life histories of myeloproliferative neoplasms inferred from phylogenies. Nature. 2022;602:162–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buck MC, Bast L, Hecker JS, Rivière J, Rothenberg-Thurley M, Vogel L, et al. Progressive disruption of hematopoietic architecture from clonal hematopoiesis to MDS. iScience. 2023;26:107328.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jakobsen NA, Turkalj S, Zeng AGX, Stoilova B, Metzner M, Nagree MS et al. Selective advantage of mutant stem cells in clonal hematopoiesis occurs by attenuating the deleterious effects of inflammation and aging. bioRxiv. 2023. https://www.biorxiv.org/content/10.1101/2023.09.12.557322v1.

  • Zeng AGX, Nagree MS, Jakobsen NA, Shah S, Murison A, Cheong J-G et al. A hematopoietic stem cell subset that retains memory of prior inflammatory stress accumulates in aging and clonal hematopoiesis. bioRxiv. 2023. https://www.biorxiv.org/content/10.1101/2023.09.11.557271v1.

  • Osman AEG, Mencia-Trinchant N, Saygin C, Moma L, Kim A, Housman G, et al. Paired bone marrow and peripheral blood samples demonstrate lack of widespread dissemination of some CH clones. Blood Adv. 2023;7:1910–4.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nowakowska MK, Kim TT, Thompson MT, Bolton KL, Deswal A, Lin SH, et al. Association of clonal hematopoiesis mutations with clinical outcomes: A systematic review and meta-analysis. Am J Hematol. 2022;97:411–20.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stein A, Metzeler K, Kubasch AS, Rommel KP, Desch S, Buettner P, et al. Clonal hematopoiesis and cardiovascular disease: deciphering interconnections. Basic Res Cardiol 2022;117:55.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heyde A, Rohde D, McAlpine CS, Zhang S, Hoyer FF, Gerold JM, et al. Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis. Cell. 2021;184:1348–1361.e22.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kessler MD, Damask A, O’Keeffe S, Banerjee N, Li D, Watanabe K, et al. Common and rare variant associations with clonal haematopoiesis phenotypes. Nature. 2022;612:301–9.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao T, Ptashkin R, Bolton KL, Sirenko M, Fong C, Spitzer B, et al. Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis. Nat Commun. 2021;12:338.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Caiado F, Pietras EM, Manz MG. Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. J Exp Med. 2021;218:e20201541.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bolton KL, Koh Y, Foote MB, Im H, Jee J, Sun CH, et al. Clonal hematopoiesis is associated with risk of severe Covid-19. Nat Commun. 2021;12:5975.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou Y, Shalhoub R, Rogers SN, Yu S, Gu M, Fabre MA, et al. Clonal hematopoiesis is not significantly associated with COVID-19 disease severity. Blood. 2022;140:1650–5.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zekavat SM, Lin SH, Bick AG, Liu A, Paruchuri K, Wang C, et al. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nat Med. 2021;27:1012–24.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Datzmann T, Trautmann F, Tesch F, Mies A, Hofbauer LC, Platzbecker U, et al. Associations of myeloid hematological diseases of the elderly with osteoporosis: A longitudinal analysis of routine health care data. Leuk Res. 2018;69:81–86.

    Article 
    PubMed 

    Google Scholar
     

  • Weidner H, Rauner M, Trautmann F, Schmitt J, Balaian E, Mies A, et al. Myelodysplastic syndromes and bone loss in mice and men. Leukemia. 2017;31:1003–7.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sano S, Oshima K, Wang Y, MacLauchlan S, Katanasaka Y, Sano M, et al. Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome. J Am Coll Cardiol. 2018;71:875–86.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377:1119–31.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schieker M, Conaghan PG, Mindeholm L, Praestgaard J, Solomon DH, Scotti C, et al. Effects of interleukin-1β inhibition on incident hip and knee replacement: Exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2020;173:509–15.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pinho S, Frenette PS. Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol. 2019;20:303–20.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Riether C, Schürch CM, Ochsenbein AF. Regulation of hematopoietic and leukemic stem cells by the immune system. Cell Death Differ. 2015;22:187–98.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mitchell CA, Verovskaya EV, Calero-Nieto FJ, Olson OC, Swann JW, Wang X, et al. Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing. Nat Cell Biol. 2023;25:30–41.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pioli PD, Casero D, Montecino-Rodriguez E, Morrison SL, Dorshkind K. Plasma Cells Are Obligate Effectors of Enhanced Myelopoiesis in Aging Bone Marrow. Immunity. 2019;51:351–366.e6.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim MJ, Valderrábano RJ, Wu JY. Osteoblast Lineage Support of Hematopoiesis in Health and Disease. J Bone Min Res. 2022;37:1823–42.

    Article 

    Google Scholar
     

  • Zhao M, Tao F, Venkatraman A, Li Z, Smith SE, Unruh J, et al. N-Cadherin-Expressing Bone and Marrow Stromal Progenitor Cells Maintain Reserve Hematopoietic Stem Cells. Cell Rep. 2019;26:652–669.e6.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kokkaliaris KD, Kunz L, Cabezas-Wallscheid N, Christodoulou C, Renders S, Camargo F, et al. Adult blood stem cell localization reflects the abundance of reported bone marrow niche cell types and their combinations. Blood. 2020;136:2296–307.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Christodoulou C, Spencer JA, Yeh SCA, Turcotte R, Kokkaliaris KD, Panero R, et al. Live-animal imaging of native haematopoietic stem and progenitor cells. Nature. 2020;578:278–83.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baccin C, Al-Sabah J, Velten L, Helbling PM, Grünschläger F, Hernández-Malmierca P, et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol. 2020;22:38–48.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Severe N, Karabacak NM, Gustafsson K, Baryawno N, Courties G, Kfoury Y, et al. Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping. Cell Stem Cell. 2019;25:570–583.e7.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tikhonova AN, Dolgalev I, Hu H, Sivaraj KK, Hoxha E, Cuesta-Domínguez Á, et al. The bone marrow microenvironment at single-cell resolution. Nature. 2019;569:222–8.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baryawno N, Przybylski D, Kowalczyk MS, Kfoury Y, Severe N, Gustafsson K, et al. A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell. 2019;177:1915–1932.e16.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alameda D, Saez B, Lara-Astiaso D, Sarvide S, Lasa M, Alignani D, et al. Characterization of freshly isolated bone marrow mesenchymal stromal cells from healthy donors and patients with multiple myeloma: transcriptional modulation of the microenvironment. Haematologica. 2020;105:e470–e473.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B. Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell. 2004;3:379–89.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu M, Wang Y, Shao JZ, Wang J, Chen W, Li YP. Cbfβ governs osteoblast−adipocyte lineage commitment through enhancing β-catenin signaling and suppressing adipogenesis gene expression. Proc Natl Acad Sci USA. 2017;114:10119–24.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kennedy DE, Knight KL. Inhibition of B Lymphopoiesis by Adipocytes and IL-1-Producing Myeloid-Derived Suppressor Cells. J Immunol. 2015;195:2666–74.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Aguilar-Navarro AG, Meza-León B, Gratzinger D, Juárez-Aguilar FG, Chang Q, Ornatsky O, et al. Human Aging Alters the Spatial Organization between CD34+ Hematopoietic Cells and Adipocytes in Bone Marrow. Stem Cell Rep. 2020;15:317–25.

    Article 
    CAS 

    Google Scholar
     

  • Pasupuleti SK, Ramdas B, Burns SS, Palam LR, Kanumuri R, Kumar R, et al. Obesity-induced inflammation exacerbates clonal hematopoiesis. J Clin Invest. 2023;133:e163968.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zioni N, Bercovich AA, Chapal-Ilani N, Bacharach T, Rappoport N, Solomon A, et al. Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis. Nat Commun. 2023;14:2070.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guidi N, Sacma M, Ständker L, Soller K, Marka G, Eiwen K, et al. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J. 2017;36:840–53.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ho YH, del Toro R, Rivera-Torres J, Rak J, Korn C, García-García A, et al. Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging. Cell Stem Cell. 2019;25:407–418.e6.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Saçma M, Pospiech J, Bogeska R, de Back W, Mallm JP, Sakk V, et al. Haematopoietic stem cells in perisinusoidal niches are protected from ageing. Nat Cell Biol. 2019;21:1309–20.

    Article 
    PubMed 

    Google Scholar
     

  • Maryanovich M, Zahalka AH, Pierce H, Pinho S, Nakahara F, Asada N, et al. Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche. Nat Med. 2018;24:782–91.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Massaro F, Corrillon F, Stamatopoulos B, Meuleman N, Lagneaux L, Bron D. Aging of Bone Marrow Mesenchymal Stromal Cells: Hematopoiesis Disturbances and Potential Role in the Development of Hematologic Cancers. Cancers. 2020;13:68.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lin TH, Gibon E, Loi F, Pajarinen J, Córdova LA, Nabeshima A, et al. Decreased osteogenesis in mesenchymal stem cells derived from the aged mouse is associated with enhanced NF-κB activity. J Orthop Res. 2017;35:281–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang DY, Wang HJ, Tan YZ. Wnt/β-Catenin Signaling Induces the Aging of Mesenchymal Stem Cells through the DNA Damage Response and the p53/p21 Pathway. PLoS One. 2011;6:e21397.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, et al. Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell. 2008;7:335–43.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hellmich C, Wojtowicz E, Moore JA, Mistry JJ, Jibril A, Johnson BB, et al. p16INK4A-dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors. Blood Adv. 2023;7:256–68.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Poudel SB, So HS, Sim HJ, Cho JS, Cho ES, Jeon YM, et al. Osteoblastic Wntless deletion differentially regulates the fate and functions of bone marrow-derived stem cells in relation to age. Stem Cells. 2021;39:103–14.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Owen-Woods C, Kusumbe A. Fundamentals of bone vasculature: Specialization, interactions and functions. Semin Cell Dev Biol. 2022;123:36–47.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507:323–8.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Acar M, Kocherlakota KS, Murphy MM, Peyer JG, Oguro H, Inra CN, et al. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature. 2015;526:126–30.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shen B, Tasdogan A, Ubellacker JM, Zhang J, Nosyreva ED, Du L, et al. A mechanosensitive peri-arteriolar niche for osteogenesis and lymphopoiesis. Nature. 2021;591:438–44.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gao X, Murphy MM, Peyer JG, Ni Y, Yang M, Zhang Y, et al. Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor. Nat Cell Biol. 2023;25:1746–57.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Raaijmakers MHGPGP. Aging of the Hematopoietic Stem Cell Niche: An Unnerving Matter. Cell Stem Cell. 2019;25:301–3.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ramasamy SK, Kusumbe AP, Schiller M, Zeuschner D, Bixel MG, Milia C, et al. Blood flow controls bone vascular function and osteogenesis. Nat Commun. 2016;7:13601.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Renders S, Svendsen AF, Panten J, Rama N, Maryanovich M, Sommerkamp P, et al. Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1. Nat Commun. 2021;12:608.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Poulos MG, Ramalingam P, Gutkin MC, Llanos P, Gilleran K, Rabbany SY, et al. Endothelial transplantation rejuvenates aged hematopoietic stem cell function. J Clin Invest. 2017;127:4163–78.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kusumbe AP, Ramasamy SK, Itkin T, Mäe MA, Langen UH, Betsholtz C, et al. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature. 2016;532:380–4.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ramalingam P, Poulos MG, Lazzari E, Gutkin MC, Lopez D, Kloss CC, et al. Chronic activation of endothelial MAPK disrupts hematopoiesis via NFKB dependent inflammatory stress reversible by SCGF. Nat Commun. 2020;11:666.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pietras EM, Mirantes-Barbeito C, Fong S, Loeffler D, Kovtonyuk LV, Zhang S, et al. Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat Cell Biol. 2016;18:607–18.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huang Z, Chen B, Liu X, Li H, Xie L, Gao Y, et al. Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis. Proc Natl Acad Sci USA. 2021;118:e2023216118.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E, et al. Comprehensive Profiling of an Aging Immune System Reveals Clonal GZMK+ CD8+ T Cells as Conserved Hallmark of Inflammaging. Immunity. 2021;54:99–115.e12.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hashimoto K, Kouno T, Ikawa T, Hayatsu N, Miyajima Y, Yabukami H, et al. Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians. Proc Natl Acad Sci USA. 2019;116:24242–51.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mogilenko DA, Shchukina I, Artyomov MN. Immune ageing at single-cell resolution. Nat Rev Immunol. 2022;22:484–98.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hennrich ML, Romanov N, Horn P, Jaeger S, Eckstein V, Steeples V, et al. Cell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline. Nat Commun. 2018;9:4004.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Herndler-Brandstetter D, Landgraf K, Tzankov A, Jenewein B, Brunauer R, Laschober GT, et al. The impact of aging on memory T cell phenotype and function in the human bone marrow. J Leukoc Biol. 2012;91:197–205.

    Article 
    PubMed 

    Google Scholar
     

  • Okhrimenko A, Grün JR, Westendorf K, Fang Z, Reinke S, Von Roth P, et al. Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory. Proc Natl Acad Sci USA. 2014;111:9229–34.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pritz T, Lair J, Ban M, Keller M, Weinberger B, Krismer M, et al. Plasma cell numbers decrease in bone marrow of old patients. Eur J Immunol. 2015;45:738–46.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fischer L, Herkner C, Kitte R, Dohnke S, Riewaldt J, Kretschmer K, et al. Foxp3+ Regulatory T Cells in Bone and Hematopoietic Homeostasis. Front Endocrinol. 2019;10:578.

    Article 

    Google Scholar
     

  • Frisch BJ, Hoffman CM, Latchney SE, LaMere MW, Myers J, Ashton J, et al. Aged marrow macrophages expand platelet-biased hematopoietic stem cells via interleukin-1B. JCI Insight. 2019;4:e124213.

    Article 
    PubMed Central 

    Google Scholar
     

  • Zou NY, Liu R, Huang M, Jiao YR, Wei J, Jiang Y, et al. Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing. Bone Res. 2024;12:6.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cook EK, Izukawa T, Young S, Rosen G, Jamali M, Zhang L, et al. Comorbid and inflammatory characteristics of genetic subtypes of clonal hematopoiesis. Blood Adv. 2019;3:2482–6.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou L, McMahon C, Bhagat T, Alencar C, Yu Y, Fazzari M, et al. Reduced SMAD7 leads to overactivation of TGF-β signaling in MDS that can be reversed by a specific inhibitor of TGF-β receptor I kinase. Cancer Res. 2011;71:955–63.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019;133:790–4.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Arranz L, Sánchez-Aguilera A, Martín-Pérez D, Isern J, Langa X, Tzankov A, et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature. 2014;512:78–81.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kovtun I, von Bonin M, Ibneeva L, Frimmel J, Middeke JM, Kunadt D, et al. Profound sympathetic neuropathy in the bone marrow of patients with acute myeloid leukemia. Leukemia. 2023;38:393–7.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mistry JJ, Young KA, Trowbridge JJ. Bone Marrow Stromal Cell Senescence Induced By Dnmt3a-Mutant Hematopoietic Stem and Progenitor Cells Accelerates Clonal Hematopoiesis and Progression to Leukemia. Blood. 2022;140:1265–1265.

    Article 

    Google Scholar
     

  • Nguyen YTM, Fujisawa M, Nguyen TB, Suehara Y, Sakamoto T, Matsuoka R, et al. Tet2 deficiency in immune cells exacerbates tumor progression by increasing angiogenesis in a lung cancer model. Cancer Sci. 2021;112:4931–43.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355:842–7.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Abplanalp WT, Cremer S, John D, Hoffmann J, Schuhmacher B, Merten M, et al. Clonal Hematopoiesis-Driver DNMT3A Mutations Alter Immune Cells in Heart Failure. Circ Res. 2021;128:216–28.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Helbling PM, Piñeiro-Yáñez E, Gerosa R, Boettcher S, Al-Shahrour F, Manz MG, et al. Global Transcriptomic Profiling of the Bone Marrow Stromal Microenvironment during Postnatal Development, Aging, and Inflammation. Cell Rep. 2019;29:3313–3330.e4.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Abegunde SO, Buckstein R, Wells RA, Rauh MJ. An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp Hematol. 2018;59:60–65.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liao M, Chen R, Yang Y, He H, Xu L, Jiang Y, et al. Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis. Acta Pharm Sin B. 2022;12:678.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sanmiguel JM, Eudy E, Loberg MA, Young KA, Mistry JJ, Mujica KD, et al. Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis. Cancer Discov. 2022;12:2763–73.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Caiado F, Kovtonyuk LV, Gonullu NG, Fullin J, Boettcher S, Manz MG. Aging drives Tet2+/− clonal hematopoiesis via IL-1 signaling. Blood. 2023;141:886–903.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boy M, Bisio V, Zhao LP, Guidez F, Schell B, Lereclus E, et al. Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation. Nat Commun. 2023;14:588.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Campillo-Marcos I, Alvarez-Errico D, Alandes RA, Mereu E, Esteller M. Single-cell technologies and analyses in hematopoiesis and hematological malignancies. Exp Hematol. 2021;98:1–13.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Triana S, Vonficht D, Jopp-Saile L, Raffel S, Lutz R, Leonce D, et al. Single-cell proteo-genomic reference maps of the hematopoietic system enable the purification and massive profiling of precisely defined cell states. Nat Immunol. 2021;22:1577–89.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Izzo F, Lee SC, Poran A, Chaligne R, Gaiti F, Gross B, et al. DNA methylation disruption reshapes the hematopoietic differentiation landscape. Nat Genet. 2020;52:378–87.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Heimlich JB, Bhat P, Parker AC, Jenkins MT, Vlasschaert C, Ulloa J et al. Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis. bioRxiv 2022. https://www.biorxiv.org/content/10.1101/2022.12.01.518580v2.

  • Wolock SL, Krishnan I, Tenen DE, Matkins V, Camacho V, Patel S, et al. Mapping Distinct Bone Marrow Niche Populations and Their Differentiation Paths. Cell Rep. 2019;28:302–311.e5.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li H, Bräunig S, Dhapolar P, Karlsson G, Lang S, Scheding S. Identification of phenotypically, functionally, and anatomically distinct stromal niche populations in human bone marrow based on single-cell RNA sequencing. Elife. 2023;12:e81656.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang J, Wu Q, Johnson CB, Pham G, Kinder JM, Olsson A, et al. In situ mapping identifies distinct vascular niches for myelopoiesis. Nature. 2021;590:457–62.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Crosse EI, Gordon-Keylock S, Rybtsov S, Binagui-Casas A, Felchle H, Nnadi NC, et al. Multi-layered Spatial Transcriptomics Identify Secretory Factors Promoting Human Hematopoietic Stem Cell Development. Cell Stem Cell. 2020;27:822–839.e8.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Calvanese V, Capellera-Garcia S, Ma F, Fares I, Liebscher S, Ng ES, et al. Mapping human haematopoietic stem cells from haemogenic endothelium to birth. Nature. 2022;604:534–40.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oetjen KA, Lindblad KE, Goswami M, Gui G, Dagur PK, Lai C, et al. Human bone marrow assessment by single-cell RNA sequencing, mass cytometry, and flow cytometry. JCI insight. 2018;3:e124928.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee NYS, Li M, Ang KS, Chen J. Establishing a human bone marrow single cell reference atlas to study ageing and diseases. Front Immunol. 2023;14:1127879.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Torlakovic EE, Brynes RK, Hyjek E, Lee SH, Kreipe H, Kremer M, et al. ICSH guidelines for the standardization of bone marrow immunohistochemistry. Int J Lab Hematol. 2015;37:431–49.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hernandez S, Lazcano R, Serrano A, Powell S, Kostousov L, Mehta J, et al. Challenges and Opportunities for Immunoprofiling Using a Spatial High-Plex Technology: The NanoString GeoMx® Digital Spatial Profiler. Front Oncol. 2022;12:2946.

    Article 

    Google Scholar
     

  • Angelo M, Bendall SC, Finck R, Hale MB, Hitzman C, Borowsky AD, et al. Multiplexed ion beam imaging of human breast tumors. Nat Med. 2014;20:436–42.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stack EC, Wang C, Roman KA, Hoyt CC. Multiplexed immunohistochemistry, imaging, and quantitation: A review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods. 2014;70:46–58.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kennedy-Darling J, Bhate SS, Hickey JW, Black S, Barlow GL, Vazquez G, et al. Highly multiplexed tissue imaging using repeated oligonucleotide exchange reaction. Eur J Immunol. 2021;51:1262.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kinkhabwala A, Herbel C, Pankratz J, Yushchenko DA, Rüberg S, Praveen P, et al. MACSima imaging cyclic staining (MICS) technology reveals combinatorial target pairs for CAR T cell treatment of solid tumors. Sci Rep. 2022;12:1911.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Weeks LD, Niroula A, Neuberg D, Wong W, Lindsley RC, Luskin MR et al. Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis. NEJM Evid. 2023;2. https://doi.org/10.1056/evidoa2200310.

  • Gu M, Kovilakam SC, Dunn WG, Marando L, Barcena C, Mohorianu I, et al. Multiparameter prediction of myeloid neoplasia risk. Nat Genet. 2023;55:1523–30.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Köhnke T, Majeti R. Clonal Hematopoiesis: From Mechanisms to Clinical Intervention. Cancer Discov. 2021;11:2987–97.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar