Aberrant Kupffer-like differentiation of hematopoietic stem cell is critical for the MDS pathogenesis in Setd2-deficient mice

Aberrant Kupffer-like differentiation of hematopoietic stem cell is critical for the MDS pathogenesis in Setd2-deficient mice

  • Issa JP. The myelodysplastic syndrome as a prototypical epigenetic disease. Blood. 2013;121:3811–7.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer. 2017;17:5–19.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kristinsson SY, Bjorkholm M, Hultcrantz M, Derolf AR, Landgren O, Goldin LR. Chronic immune stimulation might act as a trigger for the development of acute myeloid leukemia or myelodysplastic syndromes. J Clin Oncol. 2011;29:2897–903.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sallman DA, List A. The central role of inflammatory signaling in the pathogenesis of myelodysplastic syndromes. Blood. 2019;133:1039–48.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Barreyro L, Chlon TM, Starczynowski DT. Chronic immune response dysregulation in MDS pathogenesis. Blood. 2018;132:1553–60.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ganan-Gomez I, Wei Y, Starczynowski DT, Colla S, Yang H, Cabrero-Calvo M, et al. Deregulation of innate immune and inflammatory signaling in myelodysplastic syndromes. Leukemia. 2015;29:1458–69.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Varney ME, Melgar K, Niederkorn M, Smith M, Barreyro L, Starczynowski DT. Deconstructing innate immune signaling in myelodysplastic syndromes. Exp Hematol. 2015;43:587–98.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016;128:2960–75.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010;464:852–7.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zambetti NA, Ping Z, Chen S, Kenswil KJG, Mylona MA, Sanders MA, et al. Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell. 2016;19:613–27.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123:4595–611.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016;22:288–97.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ribezzo F, Snoeren IAM, Ziegler S, Stoelben J, Olofsen PA, Henic A, et al. Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome. Leukemia. 2019;33:1759–72.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518:547–51.

    Article 
    PubMed 

    Google Scholar
     

  • Hoeffel G, Chen J, Lavin Y, Low D, Almeida FF, See P, et al. C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity. 2015;42:665–78.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Guilliams M, Scott CL. Liver macrophages in health and disease. Immunity. 2022;55:1515–29.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Li W, Yang Y, Yang L, Chang N, Li L. Monocyte-derived Kupffer cells dominate in the Kupffer cell pool during liver injury. Cell Rep. 2023;42:113164.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Tran S, Baba I, Poupel L, Dussaud S, Moreau M, Gelineau A, et al. Impaired Kupffer cell self-renewal alters the liver response to lipid overload during non-alcoholic steatohepatitis. Immunity. 2020;53:627–40.e5.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Seidman JS, Troutman TD, Sakai M, Gola A, Spann NJ, Bennett H, et al. Niche-specific reprogramming of epigenetic landscapes drives myeloid cell diversity in nonalcoholic steatohepatitis. Immunity. 2020;52:1057–74.e7.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Remmerie A, Martens L, Thone T, Castoldi A, Seurinck R, Pavie B, et al. Osteopontin expression identifies a subset of recruited macrophages distinct from Kupffer cells in the fatty liver. Immunity. 2020;53:641–57.e14.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Fan N, Lavu S, Hanson CA, Tefferi A. Extramedullary hematopoiesis in the absence of myeloproliferative neoplasm: Mayo Clinic case series of 309 patients. Blood Cancer J. 2018;8:119.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Sun XJ, Wei J, Wu XY, Hu M, Wang L, Wang HH, et al. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J Biol Chem. 2005;280:35261–71.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Hu M, Sun XJ, Zhang YL, Kuang Y, Hu CQ, Wu WL, et al. Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proc Natl Acad Sci USA. 2010;107:2956–61.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Kizer KO, Phatnani HP, Shibata Y, Hall H, Greenleaf AL, Strahl BD. A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation. Mol Cell Biol. 2005;25:3305–16.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Baubec T, Colombo DF, Wirbelauer C, Schmidt J, Burger L, Krebs AR, et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature. 2015;520:243–7.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Huang H, Weng H, Zhou K, Wu T, Zhao BS, Sun M, et al. Histone H3 trimethylation at lysine 36 guides m(6)A RNA modification co-transcriptionally. Nature. 2019;567:414–9.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith OM, Misteli T. Regulation of alternative splicing by histone modifications. Science. 2010;327:996–1000.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Wen H, Li Y, Xi Y, Jiang S, Stratton S, Peng D, et al. ZMYND11 links histone H3.3K36me3 to transcription elongation and tumour suppression. Nature. 2014;508:263–8.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Li F, Mao G, Tong D, Huang J, Gu L, Yang W, et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSalpha. Cell. 2013;153:590–600.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Pfister SX, Ahrabi S, Zalmas LP, Sarkar S, Aymard F, Bachrati CZ, et al. SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability. Cell Rep. 2014;7:2006–18.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chen K, Liu J, Liu S, Xia M, Zhang X, Han D, et al. Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell. 2017;170:492–506.e14.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Park IY, Powell RT, Tripathi DN, Dere R, Ho TH, Blasius TL, et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell. 2016;166:950–62.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Yuan H, Han Y, Wang X, Li N, Liu Q, Yin Y, et al. SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell. 2020;38:350–65.e7.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Lu M, Zhao B, Liu M, Wu L, Li Y, Zhai Y, et al. Pan-cancer analysis of SETD2 mutation and its association with the efficacy of immunotherapy. NPJ Precis Oncol. 2021;5:51.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • McKinney M, Moffitt AB, Gaulard P, Travert M, De Leval L, Nicolae A, et al. The genetic basis of hepatosplenic T-cell lymphoma. Cancer Discov. 2017;7:369–79.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Mar BG, Bullinger LB, McLean KM, Grauman PV, Harris MH, Stevenson K, et al. Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia. Nat Commun. 2014;5:3469.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu X, He F, Zeng H, Ling S, Chen A, Wang Y, et al. Identification of functional cooperative mutations of SETD2 in human acute leukemia. Nat Genet. 2014;46:287–93.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Leung W, Teater M, Durmaz C, Meydan C, Chivu AG, Chadburn A, et al. SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B-cell lymphomagenesis. Cancer Discov. 2022;12:1782–803.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Parker H, Rose-Zerilli MJ, Larrayoz M, Clifford R, Edelmann J, Blakemore S, et al. Genomic disruption of the histone methyltransferase SETD2 in chronic lymphocytic leukaemia. Leukemia. 2016;30:2179–86.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Li J, Peng Z, Luo F, Chen Y. SET domain containing 2 deficiency in myelodysplastic syndrome. Front Genet. 2020;11:794.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chen BY, Song J, Hu CL, Chen SB, Zhang Q, Xu CH, et al. SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS. Blood. 2020;135:2271–85.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhang YL, Sun JW, Xie YY, Zhou Y, Liu P, Song JC, et al. Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res. 2018;28:476–90.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhou Y, Yan X, Feng X, Bu J, Dong Y, Lin P, et al. Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation. Haematologica. 2018;103:1110–23.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Chu SH, Chabon JR, Matovina CN, Minehart JC, Chen BR, Zhang J, et al. Loss of H3K36 methyltransferase SETD2 impairs V(D)J recombination during lymphoid development. iScience. 2020;23:100941.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ji Z, Sheng Y, Miao J, Li X, Zhao H, Wang J, et al. The histone methyltransferase Setd2 is indispensable for V(D)J recombination. Nat Commun. 2019;10:3353.

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ding Z, Cai T, Tang J, Sun H, Qi X, Zhang Y, et al. Setd2 supports GATA3(+)ST2(+) thymic-derived Treg cells and suppresses intestinal inflammation. Nat Commun. 2022;13:7468.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liu Y, Pop R, Sadegh C, Brugnara C, Haase VH, Socolovsky M. Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo. Blood. 2006;108:123–33.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Shim YA, Campbell T, Weliwitigoda A, Dosanjh M, Johnson P. Regulation of CD71(+)TER119(+) erythroid progenitor cells by CD45. Exp Hematol. 2020;86:53–66.e1.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Mass E, Nimmerjahn F, Kierdorf K, Schlitzer A. Tissue-specific macrophages: how they develop and choreograph tissue biology. Nat Rev Immunol. 2023;23:563–79.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Barisas DAG, Choi K. Extramedullary hematopoiesis in cancer. Exp Mol Med. 2024;56:549–58.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Jiang K, Tian K, Yu Y, Wu E, Yang M, Pan F, et al. Kupffer cells determine intrahepatic traffic of PEGylated liposomal doxorubicin. Nat Commun. 2024;15:6136.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Liu J, Zhu Z, Leung GK. Erythrophagocytosis by microglia/macrophage in intracerebral hemorrhage: from mechanisms to translation. Front Cell Neurosci. 2022;16:818602.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Soyfer EM, Fleischman AG. Myeloproliferative neoplasms – blurring the lines between cancer and chronic inflammatory disorder. Front Oncol. 2023;13:1208089.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Rodriguez-Sevilla JJ, Colla S. Inflammation in myelodysplastic syndrome pathogenesis. Semin Hematol. 2024;61:385–96.

    Article 
    PubMed 

    Google Scholar
     

  • Stubbins RJ, Platzbecker U, Karsan A. Inflammation and myeloid malignancy: quenching the flame. Blood. 2022;140:1067–74.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kesharwani P, Dash D, Koiri RK. Deciphering the role of hepcidin in iron metabolism and anemia management. J Trace Elem Med Biol. 2025;87:127591.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sun Y, Tong H, Chu X, Li Y, Zhang J, Ding Y, et al. Notch1 regulates hepatic thrombopoietin production. Blood. 2024;143:2778–90.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Merz AMA, Platzbecker U. Treatment of lower-risk myelodysplastic syndromes. Haematologica. 2025;110:330–8.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Gonzalez-Menendez P, Phadke I, Olive ME, Joly A, Papoin J, Yan H, et al. Arginine metabolism regulates human erythroid differentiation through hypusination of eIF5A. Blood. 2023;141:2520–36.

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Mass, E, I Ballesteros, M Farlik, F Halbritter, P Gunther, L Crozet, et al. Specification of tissue-resident macrophages during organogenesis. Science. 2016;353:aaf4238.

  • Simon JM, Hacker KE, Singh D, Brannon AR, Parker JS, Weiser M, et al. Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Genome Res. 2014;24:241–50.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Xie Y, Sahin M, Sinha S, Wang Y, Nargund AM, Lyu Y, et al. SETD2 loss perturbs the kidney cancer epigenetic landscape to promote metastasis and engenders actionable dependencies on histone chaperone complexes. Nat Cancer. 2022;3:188–202.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Domcke S, Bardet AF, Adrian Ginno P, Hartl D, Burger L, Schubeler D. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature. 2015;528:575–9.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Yin, Y, E Morgunova, A Jolma, E Kaasinen, B Sahu, S Khund-Sayeed, et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science. 2017;356:eaaj2239.

  • 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 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Guo Y, Xue Z, Yuan R, Li JJ, Pastor WA, Liu W. RAD: a web application to identify region associated differentially expressed genes. Bioinformatics. 2021;37:2741–3.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Wang L, You X, Ruan D, Shao R, Dai HQ, Shen W, et al. TET enzymes regulate skeletal development through increasing chromatin accessibility of RUNX2 target genes. Nat Commun. 2022;13:4709.

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Friedrich, C and O Kosmider. The mesenchymal niche in myelodysplastic syndromes. Diagnostics. 2022;12:1639.

  • Kouroukli O, Symeonidis A, Foukas P, Maragkou MK, Kourea EP. Bone marrow immune microenvironment in myelodysplastic syndromes. Cancers. 2022;14:5656.

  • Tanaka TN, Bejar R. MDS overlap disorders and diagnostic boundaries. Blood. 2019;133:1086–95.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Guryanova OA, Lieu YK, Garrett-Bakelman FE, Spitzer B, Glass JL, Shank K, et al. Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia. 2016;30:1133–42.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kuhn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science. 1995;269:1427–9.

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Georgiades P, Ogilvy S, Duval H, Licence DR, Charnock-Jones DS, Smith SK, et al. VavCre transgenic mice: a tool for mutagenesis in hematopoietic and endothelial lineages. Genesis. 2002;34:251–6.

    Article 
    PubMed 
    CAS 

    Google Scholar