T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response

T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response

  • Mesin, L., Ersching, J. & Victora, G. D. Germinal center B cell dynamics. Immunity 45, 471–482 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, M. et al. Two levels of protection for the B cell genome during somatic hypermutation. Nature 451, 841–845 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341–346 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shen, H. M., Peters, A., Baron, B., Zhu, X. & Storb, U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280, 1750–1752 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bal, E. et al. Super-enhancer hypermutation alters oncogene expression in B cell lymphoma. Nature 607, 808–815 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, C. S., Deenick, E. K., Batten, M. & Tangye, S. G. The origins, function and regulation of T follicular helper cells. J. Exp. Med. 209, 1241–1253 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Suzuki, K., Grigorova, I., Phan, T. G., Kelly, L. M. & Cyster, J. G. Visualizing B cell capture of cognate antigen from follicular dendritic cells. J. Exp. Med. 206, 1485–1493 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, X. et al. Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers. J. Exp. Med. 208, 2497–2510 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bannard, O. et al. Ubiquitin-mediated fluctuations in MHC class II facilitate efficient germinal center B cell responses. J. Exp. Med. 213, 993–1009 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ise, W. et al. T follicular helper cell-germinal center B cell interaction strength regulates entry into plasma cell or recycling germinal center cell fate. Immunity 48, 702–715 e704 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Calado, D. P. et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat. Immunol. 13, 1092–1100 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dominguez-Sola, D. et al. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat. Immunol. 13, 1083–1091 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ersching, J. et al. Germinal center selection and affinity maturation require dynamic regulation of mTORC1 kinase. Immunity 46, 1045–1058 e1046 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pae, J. et al. Cyclin D3 drives inertial cell cycling in dark zone germinal center B cells. J. Exp. Med. 218, e20201699 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Victora, G. D. et al. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143, 592–605 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gitlin, A. D. et al. T cell help controls the speed of the cell cycle in germinal center B cells. Science 349, 643–646 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gitlin, A. D., Shulman, Z. & Nussenzweig, M. C. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509, 637–640 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dominguez, P. M. et al. TET2 deficiency causes germinal center hyperplasia, impairs plasma cell differentiation, and promotes B-cell lymphomagenesis. Cancer Discov. 8, 1632–1653 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dominguez, P. M. et al. DNA methylation dynamics of germinal center B cells are mediated by AID. Cell Rep. 12, 2086–2098 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rosikiewicz, W. et al. TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis. Sci. Adv. 6, eaay5872 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shaknovich, R. et al. DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. Blood 118, 3559–3569 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ortega-Molina, A. et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat. Med. 21, 1199–1208 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Velichutina, I. et al. EZH2-mediated epigenetic silencing in germinal center B cells contributes to proliferation and lymphomagenesis. Blood 116, 5247–5255 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beguelin, W. et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 23, 677–692 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hatzi, K. et al. Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis. Nat. Immunol. 20, 86–96 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Leung, W. et al. SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B-cell lymphomagenesis. Cancer Discov. 12, 1782–1803 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, J. et al. Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment. Nat. Commun. 15, 2879 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barisic, D. et al. ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis. Cancer Cell 42, 583–604 e511 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Doane, A. S. et al. OCT2 pre-positioning facilitates cell fate transition and chromatin architecture changes in humoral immunity. Nat. Immunol. 22, 1327–1340 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bunting, K. L. et al. Multi-tiered reorganization of the genome during B cell affinity maturation anchored by a germinal center-specific locus control region. Immunity 45, 497–512 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chu, C. S. et al. Unique immune cell coactivators specify locus control region function and cell stage. Mol. Cell 80, 845–861 e810 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vilarrasa-Blasi, R. et al. Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation. Nat. Commun. 12, 651 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gorelov, R. & Hochedlinger, K. A cellular identity crisis? Plasticity changes during aging and rejuvenation. Genes Dev. 38, 823–842 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tata, P. R. & Rajagopal, J. Cellular plasticity: 1712 to the present day. Curr. Opin. Cell Biol. 43, 46–54 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Waddington, C. H. The Strategy of the Genes (Routledge, 2014).

  • Stadtfeld, M. & Hochedlinger, K. Induced pluripotency: history, mechanisms and applications. Genes Dev. 24, 2239–2263 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Di Stefano, B. et al. C/EBPalpha poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature 506, 235–239 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Eminli, S. et al. Differentiation stage determines potential of hematopoietic cells for reprogramming into induced pluripotent stem cells. Nat. Genet. 41, 968–976 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hanna, J. et al. Direct cell reprogramming is a stochastic process amenable to acceleration. Nature 462, 595–601 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bar-Nur, O., Russ, H. A., Efrat, S. & Benvenisty, N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell 9, 17–23 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, K. et al. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285–290 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ohi, Y. et al. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat. Cell Biol. 13, 541–549 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Polo, J. M. et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151, 1617–1632 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schmidt, R. & Plath, K. The roles of the reprogramming factors Oct4, Sox2 and Klf4 in resetting the somatic cell epigenome during induced pluripotent stem cell generation. Genome Biol. 13, 251 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vierbuchen, T. & Wernig, M. Molecular roadblocks for cellular reprogramming. Mol. Cell 47, 827–838 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Apostolou, E. & Hochedlinger, K. Chromatin dynamics during cellular reprogramming. Nature 502, 462–471 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huyghe, A. et al. Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity. Nat. Cell Biol. 24, 1350–1363 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stadtfeld, M., Maherali, N., Borkent, M. & Hochedlinger, K. A reprogrammable mouse strain from gene-targeted embryonic stem cells. Nat. Methods 7, 53–55 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bar-Nur, O. et al. Small molecules facilitate rapid and synchronous iPSC generation. Nat. Methods 11, 1170–1176 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lengner, C. J. et al. Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell 1, 403–415 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Polo, J. M. et al. Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells. Nat. Biotechnol. 28, 848–855 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Di Giammartino, D. C. et al. KLF4 is involved in the organization and regulation of pluripotency-associated three-dimensional enhancer networks. Nat. Cell Biol. 21, 1179–1190 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gaspar, J. A. et al. Gene expression signatures defining fundamental biological processes in pluripotent, early and late differentiated embryonic stem cells. Stem. Cells Dev. 21, 2471–2484 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Glover, C. H. et al. Meta-analysis of differentiating mouse embryonic stem cell gene expression kinetics reveals early change of a small gene set. PLoS Comput. Biol. 2, e158 (2006).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ivanova, N. B. et al. A stem cell molecular signature. Science 298, 601–604 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mikkelsen, T. S. et al. Dissecting direct reprogramming through integrative genomic analysis. Nature 454, 49–55 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ramalho-Santos, M., Yoon, S., Matsuzaki, Y., Mulligan, R. C. & Melton, D. A. ‘Stemness’: transcriptional profiling of embryonic and adult stem cells. Science 298, 597–600 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wong, D. J. et al. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2, 333–344 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yoshida, H. et al. The cis-regulatory atlas of the mouse immune system. Cell 176, 897–912 e820 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, J. et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell 143, 313–324 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beguelin, W. et al. Mutant EZH2 induces a pre-malignant lymphoma niche by reprogramming the immune response. Cancer Cell 37, 655–673 e611 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rivas, M. A. et al. Cohesin core complex gene dosage contributes to germinal center derived lymphoma phenotypes and outcomes. Front. Immunol. 12, 688493 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yusufova, N. et al. Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture. Nature 589, 299–305 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 40, 413–442 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Francesconi, M. et al. Single cell RNA-seq identifies the origins of heterogeneity in efficient cell transdifferentiation and reprogramming. Elife 8, e41627 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beguelin, W. et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell 30, 197–213 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mlynarczyk, C. et al. BTG1 mutation yields supercompetitive B cells primed for malignant transformation. Science 379, eabj7412 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Granja, J. M. et al. ArchR is a scalable software package for integrative single-cell chromatin accessibility analysis. Nat. Genet. 53, 403–411 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Guo, M. et al. A monoclonal antibody to the DEC-205 endocytosis receptor on human dendritic cells. Hum. Immunol. 61, 729–738 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Victora, G. D. et al. Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood 120, 2240–2248 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cobaleda, C., Schebesta, A., Delogu, A. & Busslinger, M. Pax5: the guardian of B cell identity and function. Nat. Immunol. 8, 463–470 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dominguez-Sola, D. et al. The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity 43, 1064–1074 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Inoue, T. et al. The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help. J. Exp. Med. 214, 1181–1198 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sander, S. et al. PI3 Kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity 43, 1075–1086 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Grosveld, F., van Staalduinen, J. & Stadhouders, R. Transcriptional regulation by (super)enhancers: from discovery to mechanisms. Annu. Rev. Genomics Hum. Genet. 22, 127–146 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Schep, A. N., Wu, B., Buenrostro, J. D. & Greenleaf, W. J. chromVAR: inferring transcription-factor-associated accessibility from single-cell epigenomic data. Nat. Methods 14, 975–978 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Koike, T., Harada, K., Horiuchi, S. & Kitamura, D. The quantity of CD40 signaling determines the differentiation of B cells into functionally distinct memory cell subsets. eLife 8, e44245 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jang, J. Y. et al. A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas. J. Clin. Invest. 132, e160767 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Langlet, F. et al. Selective inhibition of FOXO1 activator/repressor balance modulates hepatic glucose handling. Cell 171, 824–835 e818 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Willcockson, M. A. et al. H1 histones control the epigenetic landscape by local chromatin compaction. Nature 589, 293–298 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fan, Y. et al. H1 linker histones are essential for mouse development and affect nucleosome spacing in vivo. Mol. Cell. Biol. 23, 4559–4572 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Perez-Gonzalez, A., Bevant, K. & Blanpain, C. Cancer cell plasticity during tumor progression, metastasis and response to therapy. Nat. Cancer 4, 1063–1082 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Donati, G. & Amati, B. MYC and therapy resistance in cancer: risks and opportunities. Mol. Oncol. 16, 3828–3854 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jakobsen, S. T. et al. MYC activity at enhancers drives prognostic transcriptional programs through an epigenetic switch. Nat. Genet. 56, 663–674 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Petrich, A. M., Nabhan, C. & Smith, S. M. MYC-associated and double-hit lymphomas: a review of pathobiology, prognosis, and therapeutic approaches. Cancer 120, 3884–3895 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Agirre, X. et al. Long non-coding RNAs discriminate the stages and gene regulatory states of human humoral immune response. Nat. Commun. 10, 821 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ennishi, D. et al. TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma. Nat. Med. 26, 577–588 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Reddy, A. et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell 171, 481–494 e415 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schmitz, R. et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N. Engl. J. Med. 378, 1396–1407 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wright, G. W. et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer Cell 37, 551–568 e514 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • DuPage, M. & Bluestone, J. A. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat. Rev. Immunol. 16, 149–163 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ge, Y. & Fuchs, E. Stretching the limits: from homeostasis to stem cell plasticity in wound healing and cancer. Nat. Rev. Genet. 19, 311–325 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Flavahan, W. A., Gaskell, E. & Bernstein, B. E. Epigenetic plasticity and the hallmarks of cancer. Science 357, eaal2380 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pitarresi, J. R. & Stanger, B. Z. Cellular origins and lineage plasticity in cancer. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a041389 (2023).

    Article 

    Google Scholar
     

  • Yuan, S., Norgard, R. J. & Stanger, B. Z. Cellular plasticity in cancer. Cancer Discov. 9, 837–851 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Herrera, E., Martinez, A. C. & Blasco, M. A. Impaired germinal center reaction in mice with short telomeres. EMBO J. 19, 472–481 (2000).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, B. T., Lee, S. C., Marin, E., Ryan, D. H. & Insel, R. A. Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J. Immunol. 159, 1068–1071 (1997).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guldenpfennig, C., Teixeiro, E. & Daniels, M. NF-kB’s contribution to B cell fate decisions. Front. Immunol. 14, 1214095 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pelzer, C. & Thome, M. IKKα takes control of canonical NF-kB activation. Nat. Immunol. 12, 815–816 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cao, Y., Yi, Y., Han, C. & Shi, B. NF-kB signaling pathway in tumor microenvironment. Front. Immunol. 15, 1476030 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jiang, C. et al. Innate immunity and the NF-κB pathway control prostate stem cell plasticity, reprogramming and tumor initiation. Nat. Cancer 6, 1537–1558 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sardina, J. L. et al. Transcription factors drive Tet2-mediated enhancer demethylation to reprogram cell fate. Cell Stem Cell 23, 905–906 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Boller, S. et al. Pioneering activity of the C-terminal domain of EBF1 shapes the chromatin landscape for B cell programming. Immunity 44, 527–541 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Apostolou, E. & Stadtfeld, M. Cellular trajectories and molecular mechanisms of iPSC reprogramming. Curr. Opin. Genet. Dev. 52, 77–85 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cyster, J. G. Germinal centers: gaining strength from the dark side. Immunity 43, 1026–1028 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rais, Y. et al. Deterministic direct reprogramming of somatic cells to pluripotency. Nature 502, 65–70 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Esteller, M. et al. The epigenetic hallmarks of cancer. Cancer Discov. 14, 1783–1809 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Loh, J. J. & Ma, S. Hallmarks of cancer stemness. Cell Stem Cell 31, 617–639 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Weinberg, O. K. & Arber, D. A. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia 24, 1844–1851 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chang, K. C. et al. Stem cell characteristics promote aggressiveness of diffuse large B-cell lymphoma. Sci. Rep. 10, 21342 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Martinez-Climent, J. A., Fontan, L., Gascoyne, R. D., Siebert, R. & Prosper, F. Lymphoma stem cells: enough evidence to support their existence? Haematologica 95, 293–302 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mlynarczyk, C., Fontan, L. & Melnick, A. Germinal center-derived lymphomas: the darkest side of humoral immunity. Immunol. Rev. 288, 214–239 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, F. et al. Degree of stemness predicts micro-environmental response and clinical outcomes of diffuse large B-cell lymphoma and identifies a potential targeted therapy. Front. Immunol. 13, 1012242 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • in Guide for the Care and Use of Laboratory Animals The National Academies Collection: Reports funded by National Institutes of Health (National Academies Press, 2011).

  • Xia, M. et al. BCL10 mutations define distinct dependencies guiding precision therapy for DLBCL. Cancer Discov. 12, 1922–1941 (2022).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Craig, R. et al. IL-1β stimulates a novel axis within the NFkB pathway in endothelial cells regulated by IKKα and TAK-1. Biochem. Pharmacol. 232, 116736 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Riley, C. et al. Design and synthesis of novel aminoindazole-pyrrolo[2,3-b]pyridine inhibitors of IKKα that selectively perturb cellular non-canonical NF-kB signalling. Molecules https://doi.org/10.3390/molecules29153515 (2024).

  • Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 e3529 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liao, Y., Smyth, G. K. & Shi, W. The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Res. 47, e47 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hanzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14, 7 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pelham-Webb, B. et al. H3K27ac bookmarking promotes rapid post-mitotic activation of the pluripotent stem cell program without impacting 3D chromatin reorganization. Mol. Cell 81, 1732–1748 e1738 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar