T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas Through H3K9me3 Modifications

Overview

Journal Adv Healthc Mater

Specialties Biomedical Engineering
Biotechnology

Date 2024 Jun 5

PMID 38837879

Authors

Lucy S Britto

Deepali Balasubramani

Sona Desai

Phunterion Phillips

Neev Trehan

Ethel Cesarman

Jean L Koff

Ankur Singh

Affiliations

Soon will be listed here.

Abstract

Activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a subtype associated with poor survival outcomes. Despite identifying therapeutic targets through molecular characterization, targeted therapies have limited success. New strategies using immune-competent tissue models are needed to understand how DLBCL cells evade treatment. Here, synthetic hydrogel-based lymphoma organoids are used to demonstrate how signals in the lymphoid tumor microenvironment (Ly-TME) can alter B cell receptor (BCR) signaling and specific histone modifications, tri-methylation of histone 3 at lysine 9 (H3K9me3), dampening the effects of BCR pathway inhibition. Using imaging modalities, T cells increase DNA methyltransferase 3A expression and cytoskeleton formation in proximal ABC-DLBCL cells, regulated by H3K9me3. Expansion microscopy on lymphoma organoids reveals T cells increase the size and quantity of segregated H3K9me3 clusters in ABC-DLBCL cells. Findings suggest the re-organization of higher-order chromatin structures that may contribute to evasion or resistance to therapy via the emergence of novel transcriptional states. Treating ABC-DLBCL cells with a G9α histone methyltransferase inhibitor reverses T cell-mediated modulation of H3K9me3 and overcomes T cell-mediated attenuation of treatment response to BCR pathway inhibition. This study emphasizes the Ly-TME's role in altering DLBCL fate and suggests targeting aberrant signaling and microenvironmental cross-talk that can benefit high-risk patients.

Citing Articles

T Cells Spatially Regulate B Cell Receptor Signaling in Lymphomas through H3K9me3 Modifications.

Britto L, Balasubramani D, Desai S, Phillips P, Trehan N, Cesarman E Adv Healthc Mater. 2024; 14(5):e2401192.

PMID: 38837879 PMC: 11617604. DOI: 10.1002/adhm.202401192.

References

Zhu F, Crombie J, Ni W, Hoang N, Garg S, Hackett L . Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax. Haematologica. 2023; 109(1):186-199. PMC: 10772509. DOI: 10.3324/haematol.2023.283245. View

Nagel D, Spranger S, Vincendeau M, Grau M, Raffegerst S, Kloo B . Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell. 2012; 22(6):825-37. DOI: 10.1016/j.ccr.2012.11.002. View

Hsu C, Chang K, Chuang T, Chu M, Lin P, Liu H . High G9a Expression in DLBCL and Its Inhibition by Niclosamide to Induce Autophagy as a Therapeutic Approach. Cancers (Basel). 2023; 15(16). PMC: 10452841. DOI: 10.3390/cancers15164150. View

Yuan Y, Wang Q, Paulk J, Kubicek S, Kemp M, Adams D . A small-molecule probe of the histone methyltransferase G9a induces cellular senescence in pancreatic adenocarcinoma. ACS Chem Biol. 2012; 7(7):1152-7. PMC: 3401036. DOI: 10.1021/cb300139y. View

Chapuy B, Stewart C, Dunford A, Kim J, Kamburov A, Redd R . Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018; 24(5):679-690. PMC: 6613387. DOI: 10.1038/s41591-018-0016-8. View

Yao W, Wang J, Zhu L, Jia X, Xu L, Tian X . Epigenetic Regulator KDM4D Restricts Tumorigenesis Modulating SYVN1/HMGB1 Ubiquitination Axis in Esophageal Squamous Cell Carcinoma. Front Oncol. 2021; 11:761346. PMC: 8606580. DOI: 10.3389/fonc.2021.761346. View

Beguelin W, Popovic R, Teater M, Jiang Y, Bunting K, Rosen M . EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5):677-92. PMC: 3681809. DOI: 10.1016/j.ccr.2013.04.011. View

Chambwe N, Kormaksson M, Geng H, De S, Michor F, Johnson N . Variability in DNA methylation defines novel epigenetic subgroups of DLBCL associated with different clinical outcomes. Blood. 2014; 123(11):1699-708. PMC: 3954051. DOI: 10.1182/blood-2013-07-509885. View

Shou Y, Johnson S, Quek Y, Li X, Tay A . Integrative lymph node-mimicking models created with biomaterials and computational tools to study the immune system. Mater Today Bio. 2022; 14:100269. PMC: 9062348. DOI: 10.1016/j.mtbio.2022.100269. View

Clarke K, Young C, Liberante F, McMullin M, Thompson A, Mills K . The histone deacetylase inhibitor Romidepsin induces as a cascade of differential gene expression and altered histone H3K9 marks in myeloid leukaemia cells. Oncotarget. 2019; 10(37):3462-3471. PMC: 6544403. DOI: 10.18632/oncotarget.26877. View

10.

Zhang X, Huang Y, Shi X . Emerging roles of lysine methylation on non-histone proteins. Cell Mol Life Sci. 2015; 72(22):4257-72. PMC: 11114002. DOI: 10.1007/s00018-015-2001-4. View

11.

Madrazo E, Ruano D, Abad L, Alonso-Gomez E, Sanchez-Valdepenas C, Gonzalez-Murillo A . G9a Correlates with VLA-4 Integrin and Influences the Migration of Childhood Acute Lymphoblastic Leukemia Cells. Cancers (Basel). 2018; 10(9). PMC: 6162492. DOI: 10.3390/cancers10090325. View

12.

Obino D, Farina F, Malbec O, Saez P, Maurin M, Gaillard J . Actin nucleation at the centrosome controls lymphocyte polarity. Nat Commun. 2016; 7:10969. PMC: 4802043. DOI: 10.1038/ncomms10969. View

13.

He M, Kridel R . Treatment resistance in diffuse large B-cell lymphoma. Leukemia. 2021; 35(8):2151-2165. DOI: 10.1038/s41375-021-01285-3. View

14.

Fontan L, Goldstein R, Casalena G, Durant M, Teater M, Wilson J . Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL. Blood. 2020; 137(6):788-800. PMC: 7885826. DOI: 10.1182/blood.2019004713. View

15.

Du J, Johnson L, Jacobsen S, Patel D . DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol. 2015; 16(9):519-32. PMC: 4672940. DOI: 10.1038/nrm4043. View

16.

Crisp M, Liu Q, Roux K, Rattner J, Shanahan C, Burke B . Coupling of the nucleus and cytoplasm: role of the LINC complex. J Cell Biol. 2005; 172(1):41-53. PMC: 2063530. DOI: 10.1083/jcb.200509124. View

17.

Guler G, Tindell C, Pitti R, Wilson C, Nichols K, KaiWai Cheung T . Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure. Cancer Cell. 2017; 32(2):221-237.e13. DOI: 10.1016/j.ccell.2017.07.002. View

18.

Garcia-Dominguez D, Hontecillas-Prieto L, Palazon-Carrion N, Jimenez-Cortegana C, Sanchez-Margalet V, de la Cruz-Merino L . Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics. Cancers (Basel). 2022; 14(6). PMC: 8946119. DOI: 10.3390/cancers14061469. View

19.

Burger J, Wiestner A . Targeting B cell receptor signalling in cancer: preclinical and clinical advances. Nat Rev Cancer. 2018; 18(3):148-167. DOI: 10.1038/nrc.2017.121. View