Pathogenesis of Germinal Centre Derived B Cell Lymphomas
Many of the commonest human lymphomas (including follicular, diffuse large B cell and Burkitt lymphomas) develop from a specific stage of B lymphocyte differentiation termed the Germinal Centre. Normal B lymphocytes form part of our adaptive immune system. B cells encountering a foreign antigen in the context of T cell help initiate the formation of transient microanatomical structures termed germinal centres. Within germinal centres B cells undergo multiple rounds of intense proliferation coupled with somatic hypermutation of the immunoglobulin genes that alter the affinity for antigen. Those with greater affinity for antigen successfully compete for T cell help before exiting the germinal centre as immunoglobulin secreting plasma cells or memory B cells, whereas less competitive B cells default to apoptosis. Rapidly changing, but tightly controlled, programmes of gene expression determine successive cell fate choices during the germinal centre reaction. It is the loss of this tight control and the resulting corruption of cell fate choices within the germinal centre that results in the development of malignant lymphoma and that forms the focus of my group’s research.
The networks of transcription factors that regulate the germinal centre reaction have been well characterised in recent years. Their importance is underscored by the finding of recurrent somatic mutation in these transcriptional regulators in next generation sequencing studies of GC derived lymphomas. It has recently become clear that a major tier of regulation is also imposed in a highly dynamic fashion at the level of translation. Importantly, translation control is invisible to conventional gene expression profiling techniques such as microarray or RNA-seq and so the contribution of translational regulation to the control of either normal or malignant gene expression remains poorly studied. A particular focus of our group is the use of transcriptome wide translational profiling to understand how normal gene expression becomes corrupted at the level of translation during the development of lymphoma. Furthermore, we wish to reveal how this corruption of translation is brought about by somatic mutation of RNA-binding proteins that control translation (translation factors) and by the activation of oncogenic signalling pathways that regulate the activity of these translation factors. Finally we wish to characterise how new therapeutic agents that are entering trials for lymphoma may exert some of their effect though changes in translation and conversely how resistance to these agents may arise by feedback mechanisms acting at the level of mRNA translation.
Keywords: B-cell, Germinal Centre, Lymphoma, Translation, RNA-binding protein
Clinical conditions: Diffuse Large B Cell Lymphoma, Burkitt Lymphoma, Follicular Lymphoma
Methodologies: RNA-Seq, Ribosome Profiling, iCLIP, Primary human lymphocyte culture and transduction
Martin Turner, Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge
Brian Huntly, Department of Haematology, Cambridge
George Vassiliou, Department of Haematology, Cambridge
Shamith Samarajiwa, Integrative Systems Biomedicine Group, MRC Cancer Unit, Cambridge
Mangolini M, Maiques-Diaz A, Charalampopoulou S, Gerhard-Hartmann E, Bloehdorn J, Moore A, Giachetti G, Lu J, Roamio Franklin VN, Chilamakuri CSR, Moutsopoulos I, Rosenwald A, Stilgenbauer S, Zenz T, Mohorianu I, D’Santos C, Deaglio S, Hodson DJ, Martin-Subero JI, Ringshausen I. Viral transduction of primary human lymphoma B cells reveals mechanisms of NOTCH-mediated immune escape. Nat Commun. 2022 Oct 20;13(1):6220.
Bulley SJ, Santarsieri A, Lentell IC, O’Sullivan B, Hodson A, Firth O, Sadullah S, Follows AM, Karanth M, Min SY, Fowler A, Russell J, Uttenthal BJ, Hodson DJ, Follows GA. Managing relapsed refractory lymphoma with palliative oral chemotherapy: A multicentre retrospective study. EJHaem. 2022 Sep 2;3(4):1316-1320.
Machado HE, Mitchell E, Øbro NF, Kübler K, Davies M, Leongamornlert D, Cull A, Maura F, Sanders MA, Cagan ATJ, McDonald C, Belmonte M, Shepherd MS, Vieira Braga FA, Osborne RJ, Mahbubani K, Martincorena I, Laurenti E, Green AR, Getz G, Polak P, Saeb-Parsy K, Hodson DJ, Kent DG, Campbell PJ. Diverse mutational landscapes in human lymphocytes. Nature. 2022 Aug;608(7924):724-732.
Molecular subclusters of follicular lymphoma: a report from the UK’s Haematological Malignancy Research Network. Blood Adv. 2022 Apr 1:bloodadvances.2021005284.
SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma. Blood. 2020 Oct 8:blood.2021012081.
Diffuse large B-cell lymphoma genetics – simplifying the subtyping. Br J Haematol. 2021 Sep 7.
Molecular profiling in diffuse large B-cell lymphoma: why so many types of subtypes? Br J Haematol. 2021 Aug 31.
Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis. Mol Cell. 2021 Oct 7;81(19):4059-4075.e11.
SGK1 mutations in DLBCL generate hyperstable protein neoisoforms that promote AKT independence. Blood. 2021 Sep 16;138(11):959-964.
Genetic manipulation and immortalized culture of ex vivo primary human germinal center B cells. Nat Protoc. 2021 Apr 9.
Umbralisib, a Dual PI3Kδ/CK1ε Inhibitor in Patients With Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2021 Mar 8:JCO2003433.
Caeser R, Walker I, Gao J, Shah N, Rasso-Barnett L, Anand S, Martin JE, Hodson DJ. Acquired CARD11 mutation promotes BCR independence in Diffuse Large B Cell Lymphoma. JCO Precis Oncol. 2021;5:145-152.
Morschhauser F, Dyer MJS, Walter HS, Danilov AV, Ysebaert L, Hodson DJ, Fegan C, Rule SA, Radford J, Cartron G, Bouabdallah K, Davies AJ, Spurgeon S, Rajakumaraswamy N, Li B, Humeniuk R, Huang X, Bhargava P, Jürgensmeier JM, Salles G. Phase 1b study of tirabrutinib in combination with idelalisib or entospletinib in previously treated B-cell lymphoma. Leukemia. 2020 Dec 17.
Sommermann T, Yasuda T, Ronen J, Wirtz T, Weber T, Sack U, Caeser R, Zhang J, Li X, Chu VT, Jauch A, Unger K, Hodson DJ, Akalin A, Rajewsky K. Functional Interplay of Epstein-Barr Virus Oncoproteins in a Mouse Model of B Cell Lymphomagenesis. Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14421-14432.
Lacy SE, Barrans SL, Beer PA, Painter D, Smith AG, Roman E, Cooke SL, Ruiz C, Glover P, Van Hoppe SJL, Webster N, Campbell PJ, Tooze RM, Patmore R, Burton C, Crouch S, Hodson DJ. Targeted Sequencing in DLBCL, Molecular Subtypes, and Outcomes: A Haematological Malignancy Research Network Report Blood. 2020 May 14;135(20):1759-1771
Caeser R, Di Re M, Krupka JA, Gao J, Lara-Chica M, Dias JML, Cooke SL, Fenner R, Usheva Z, Runge HFP, Beer PA, Eldaly H, Pak HK, Park CS, Vassiliou GS, Huntly BJP, Mupo A, Bashford-Rogers RJM, Hodson DJ. Genetic modification of primary human B cells to model high-grade lymphoma. Nat Commun. 2019 Oct 4;10(1):4543
Hodson DJ, Screen M, Turner M. RNA-binding proteins in hematopoiesis and hematological malignancy. Blood. 2019 May 30;133(22):2365-2373.
Caeser R, Collord G, Yao WQ, Chen Z, Vassiliou GS, Beer PA, Du MQ, Scott MA, Follows GA, Hodson DJ. Targeting MEK in vemurafenib-resistant hairy cell leukemia. Leukemia. 2019 Feb;33(2):541-545. doi: 10.1038/s41375-018-0270-2
Rui L, Drennan AC, Ceribelli M, Zhu F, Wright GW, Huang DW, Xiao W, Li Y, Grindle KM, Lu L, Hodson DJ, Shaffer AL, Zhao H, Xu W, Yang Y, Staudt LM. Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):E7260-E7267.
Malcolm TI, Hodson DJ, Macintyre EA, Turner SD. Challenging perspectives on the cellular origins of lymphoma. Open Biol. 2016 Sep;6(9). pii: 160232.
Galloway A, Saveliev A, Lukasiak S, Hodson DJ, Bolland D, Ahlfors H, Monzón-Casanova E, Ciullini Mannurita S, Bell LS, Andrews S, Díaz-Muñoz MD, Corcoran A, and Turner M. RNA binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence. Science 2016; 352 (6284):453-9
Hodson DJ, Shaffer AL, Xiao W, Wright GW, Schmitz R, Phelan JD, Yang Y, Webster DE, Rui L, Kohlhammer H, Nakagawa M, Waldmann TA, Staudt LM. Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2. Proc Natl Acad Sci U S A. 2016 Mar 18.
Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, Wright G, Shaffer A, Hodson DJ, Buras E, Liu X, Powell J, Yang Y, Xu W, Zhao H, Kohlhammer H, Rosenwald A, Kluin P, Müller-Hermelink HK, Ott G, Gascoyne RD, Connors JC, Rimsza LM, Campo E, Jaffe E, Delabie J, Smeland EB, Ogwang MD, Reynolds SJ, Fisher RI, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Pittaluga S, Wilson W, Waldmann TA, Rowe M, Mbulaiteye SM, Rickinson AB, and Staudt LM. Burkitt Lymphoma Pathogenesis and Therapeutic Targets from Structural and Functional Genomics. Nature 2012; 490:116-120
Turner M, Hodson DJ. An emerging role of RNA-binding proteins as multifunctional regulators of lymphocyte development and function. Immunology Reviews 2012 May; (115):161-185.
Turner M, Hodson D. Regulation of lymphocyte development and function by RNA-binding proteins. Curr Opin Immunol 2012 Apr; 24(2):160-5.
Hodson DJ, Janas ML, Galloway A, Bell SE, Andrews S, Li CM, Pannell RP, Siebel CW, MacDonald HR, De Keersmaecker K, Adolfo A, Ferrando AA, Grutz G and Martin Turner M. Deletion of the RNA-binding proteins Zfp36l1 and Zfp36l2 leads to perturbed thymic development and T-lymphoblastic leukaemia. Nature Immunology 2010 Aug; 11(8):717-24.
Gururajan M, Haga CL, Das S, Leu CM, Hodson D, Josson S, Turner M, Cooper MD. MicroRNA 125b inhibition of B cell differentiation in germinal centers. Int Immunol Jul; 22(7):583-92.
Hodson DJ, Turner M. The role of PI3K signaling in the B cell response to antigen. Adv Exp Med Biol 2009; 633:43-53.
Hussain N, Hodson D, Marcus R, Baglin T, Luddington R. The biphasic transmittance waveform: an early marker of sepsis in patients with neutropenia. Thromb Haemost 2008 Jul; 100(1):146-8.
Janas ML, Hodson D, Stamataki Z, Hill S, Welch K, Gambardella L, Trotman LC, Pandolfi PP, Vigorito E, Turner M. The effect of deleting p110delta on the phenotype and function of PTEN deficient B cells. Journal of Immunology 2008 Jan 15; 180(2):739-46.
Hodson DJ, Bowles KM, Cooke LJ, Kläger SL, Powell GA, Laing RJ, Grant JW, Williams MV, Burnet NG, Marcus RE. Primary Central Nervous System Lymphoma (PCNSL): A single centre experience of 55 unselected cases. Clinical Oncology 2005; 17(3):185–191.
Hodson DJ, Gatward G, Erber W. Azurophilic granules in acute lymphoblastic leukaemia resulting from abundant mitochondria. British Journal Haematology 2004; 125:265.