Double hit lymphoma: from biology to therapeutic implications

References

• Campo E, Swerdlow SH, Harris NL, et al. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019–5032.
   PubMed Web of Science ®Google Scholar
• Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23(22):5027–5033.
   PubMed Web of Science ®Google Scholar
• Mounier N, Briere J, Gisselbrecht C, et al. Rituximab plus CHOP (R-CHOP) overcomes bcl-2–associated resistance to chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL). Blood. 2003;101(11):4279–4284.
   PubMed Web of Science ®Google Scholar
• A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329(14):987–994.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Sehn LH, Rademaker AW, et al. An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood. 2014;123(6):837–842.
   PubMed Web of Science ®Google Scholar
• Dunleavy K, Roschewski M, Wilson WH. Precision treatment of distinct molecular subtypes of diffuse large B-cell lymphoma: ascribing treatment based on the molecular phenotype. Clin Cancer Res. 2014;20(20):5182–5193.
   PubMed Web of Science ®Google Scholar
• Scott DW, Mottok A, Ennishi D, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33:2848–2856.
   PubMed Web of Science ®Google Scholar
• Lenz G, Wright GW, Emre NC, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008;105(36):13520–13525.
   PubMed Web of Science ®Google Scholar
• Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–511.
   PubMed Web of Science ®Google Scholar
• Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med. 2010;362(15):1417–1429.
   PubMed Web of Science ®Google Scholar
• Blenk S, Engelmann J, Weniger M, et al. Germinal center B cell-like (GCB) and activated B cell-like (ABC) type of diffuse large B cell lymphoma (DLBCL): analysis of molecular predictors, signatures, cell cycle state and patient survival. Cancer Inform. 2007;3:399–420.
   PubMedGoogle Scholar
• Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113(24):6069–6076.
   PubMed Web of Science ®Google Scholar
• Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922–926.
   PubMed Web of Science ®Google Scholar
• Nowakowski GS, LaPlant B, Macon WR, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J Clin Oncol. 2015;33(3):251–257.
   PubMed Web of Science ®Google Scholar
• Vitolo U, Chiappella A, Franceschetti S, et al. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014;15(7):730–737.
   PubMed Web of Science ®Google Scholar
• Taub R, Kirsch I, Morton C, et al. Translocation of the c-myc gene into the immunoglobulin heavy chain locus in human Burkitt lymphoma and murine plasmacytoma cells. Proc Natl Acad Sci U S A. 1982;79(24):7837–7841.
   PubMed Web of Science ®Google Scholar
• Nakamura N, Nakamine H, Tamaru J, et al. The distinction between Burkitt lymphoma and diffuse large B-Cell lymphoma with c-myc rearrangement. Mod Pathol. 2002;15(7):771–776.
   PubMed Web of Science ®Google Scholar
• Meyer N, Penn LZ. Reflecting on 25 years with MYC. Nat Rev Cancer. 2008;8(12):976–990.
   PubMed Web of Science ®Google Scholar
• Dang CV. MYC on the path to cancer. Cell. 2012;149(1):22–35.
   PubMed Web of Science ®Google Scholar
• Smith SM, Anastasi J, Cohen KS, et al. The impact of MYC expression in lymphoma biology: beyond Burkitt lymphoma. Blood Cells Mol Dis. 2010;45(4):317–323.
   PubMed Web of Science ®Google Scholar
• Snuderl M, Kolman OK, Chen Y-B, et al. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol. 2010;34(3):327–340.
   PubMed Web of Science ®Google Scholar
• Arcinas M, Heckman CA, Mehew JW, et al. Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma. Cancer Res. 2001;61(13):5202–5206.
   PubMed Web of Science ®Google Scholar
• Dunleavy K. Double-hit lymphomas: current paradigms and novel treatment approaches. Hematology Am Soc Hematol Educ Program. 2014;2014(1):107–112.
   PubMed Web of Science ®Google Scholar
• Lin P, Medeiros LJ. The impact of MYC rearrangements and “double hit” abnormalities in diffuse large B-cell lymphoma. Curr Hematol Malig Rep. 2013;8(3):243–252.
   PubMed Web of Science ®Google Scholar
• Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452–3459.
   PubMed Web of Science ®Google Scholar
• Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3460–3467.
   PubMed Web of Science ®Google Scholar
• Horn H, Ziepert M, Becher C, et al. MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma. Blood. 2013;121(12):2253–2263.
   PubMed Web of Science ®Google Scholar
• Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121(20):4021–4031; quiz 4250.
   Web of Science ®Google Scholar
• Wang XJ, Medeiros LJ, Lin P, et al. MYC cytogenetic status correlates with expression and has prognostic significance in patients with MYC/BCL2 protein double-positive diffuse large B-cell lymphoma. Am J Surg Pathol. 2015;39(9):1250–1258.
   PubMed Web of Science ®Google Scholar
• Swerdlow SH. Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC. Hematology Am Soc Hematol Educ Program. 2014;2014(1):90–99.
   PubMed Web of Science ®Google Scholar
• Klapproth K, Wirth T. Advances in the understanding of MYC-induced lymphomagenesis. Br J Haematol. 2010;149(4):484–497.
   PubMed Web of Science ®Google Scholar
• Lüscher B, Vervoorts J. Regulation of gene transcription by the oncoprotein MYC. Gene. 2012;494(2):145–160.
   PubMed Web of Science ®Google Scholar
• Li H, Nepal RM, Martin A, et al. Induction of apoptosis in Eμ-myc lymphoma cells in vitro and in vivo through calpain inhibition. Exp Hematol. 2012;40(7):548–563 e542.
   PubMed Web of Science ®Google Scholar
• Ott G, Rosenwald A, Campo E. Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification. Blood. 2013;122(24):3884–3891.
   PubMed Web of Science ®Google Scholar
• Scheller H, Tobollik S, Kutzera A, et al. c-Myc overexpression promotes a germinal center-like program in Burkitt’s lymphoma. Oncogene. 2010;29(6):888–897.
   PubMed Web of Science ®Google Scholar
• Weilemann A, Grau M, Erdmann T, et al. Essential role of IRF4 and MYC signaling for survival of anaplastic large cell lymphoma. Blood. 2015;125(1):124–132.
   PubMed Web of Science ®Google Scholar
• Flatley E, Chen AI, Zhao X, et al. Aberrations of MYC are a common event in B-cell prolymphocytic leukemia. Am J Clin Pathol. 2014;142(3):347–354.
   PubMed Web of Science ®Google Scholar
• Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010;11(2):114–120.
   PubMed Web of Science ®Google Scholar
• Aukema SM, Siebert R, Schuuring E, et al. Double-hit B-cell lymphomas. Blood. 2011;117(8):2319–2331.
   PubMed Web of Science ®Google Scholar
• Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature. 2001;412(6844):341–346.
   PubMed Web of Science ®Google Scholar
• Choe JY, Yun JY, Na HY, et al. MYC overexpression correlates with MYC amplification or translocation, and is associated with poor prognosis in mantle cell lymphoma. Histopathology. 2015;68(3):442–449.
   PubMed Web of Science ®Google Scholar
• Dave SS, Fu K, Wright GW, et al. Molecular diagnosis of Burkitt’s lymphoma. N Engl J Med. 2006;354(23):2431–2442.
   PubMed Web of Science ®Google Scholar
• Albihn A, Johnsen JI, Henriksson MA. MYC in oncogenesis and as a target for cancer therapies. Adv Cancer Res. 2010;107:163–224.
   PubMed Web of Science ®Google Scholar
• Bertrand P, Bastard C, Maingonnat C, et al. Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas. Leukemia. 2007;21(3):515–523.
   PubMed Web of Science ®Google Scholar
• Stasik CJ, Nitta H, Zhang W, et al. Increased MYC gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma. Haematologica. 2010;95(4):597–603.
   PubMed Web of Science ®Google Scholar
• Xu X, Zhang L, Wang Y, et al. Double-hit and triple-hit lymphomas arising from follicular lymphoma following acquisition of MYC: report of two cases and literature review. Int J Clin Exp Pathol. 2013;6(4):788–794.
   PubMed Web of Science ®Google Scholar
• Pillai RK, Sathanoori M, Van Oss SB, et al. Double-hit B-cell lymphomas with BCL6 and MYC translocations are aggressive, frequently extranodal lymphomas distinct from BCL2 double-hit B-cell lymphomas. Am J Surg Pathol. 2013;37(3):323–332.
   PubMed Web of Science ®Google Scholar
• Yoshida M, Ichikawa A, Miyoshi H, et al. Clinicopathological features of double-hit B-cell lymphomas with MYC and BCL2, BCL6 or CCND1 rearrangements. Pathol Int. 2015;65:519–527.
   PubMed Web of Science ®Google Scholar
• Macpherson N, Lesack D, Klasa R, et al. Small noncleaved, non-Burkitt’s (Burkit-Like) lymphoma: cytogenetics predict outcome and reflect clinical presentation. J Clin Oncol. 1999;17(5):1558–1567.
   PubMed Web of Science ®Google Scholar
• Wang W, Hu S, Lu X, et al. Triple-hit B-cell lymphoma with MYC, BCL2, and BCL6 translocations/rearrangements: clinicopathologic features of 11 cases. Am J Surg Pathol. 2015;39(8):1132–1139.
   PubMed Web of Science ®Google Scholar
• Tomita N. BCL2 and MYC dual-hit lymphoma/leukemia. J Clin Exp Hematop. 2011;51(1):7–12.
   PubMedGoogle Scholar
• Boerma EG, Siebert R, Kluin PM, et al. Translocations involving 8q24 in Burkitt lymphoma and other malignant lymphomas: a historical review of cytogenetics in the light of todays knowledge. Leukemia. 2009;23(2):225–234.
   PubMed Web of Science ®Google Scholar
• Sanders L, Jayne S, Kennedy B, et al. A double hit CD10-negative B-cell lymphoma with t(3;8)(q27;q24) leading to juxtaposition of the BCL6 and MYC loci associated with good clinical outcome. Case Rep Hematol. 2014;2014:120714.
   PubMedGoogle Scholar
• Akasaka T, Akasaka H, Ueda C, et al. Molecular and clinical features of non-Burkitt’s, diffuse large-cell lymphoma of B-cell type associated with the c-MYC/immunoglobulin heavy-chain fusion gene. J Clin Oncol. 2000;18(3):510–518.
   PubMed Web of Science ®Google Scholar
• Nitsu N, Okamoto M, Miura I, et al. Clinical significance of 8q24/c-MYC translocation in diffuse large B-cell lymphoma. Cancer Sci. 2009;100(2):233–237.
   PubMed Web of Science ®Google Scholar
• Muñoz-Mármol AM, Sanz C, Tapia G, et al. MYC status determination in aggressive B-cell lymphoma: the impact of FISH probe selection. Histopathology. 2013;63(3):418–424.
   PubMed Web of Science ®Google Scholar
• Green TM, Nielsen O, De Stricker K, et al. High levels of nuclear MYC protein predict the presence of MYC rearrangement in diffuse large B-cell lymphoma. Am J Surg Pathol. 2012;36(4):612–619.
   PubMed Web of Science ®Google Scholar
• Agarwal R, Lade S, Liew D, et al. Role of immunohistochemistry in the era of genetic testing in MYC-positive aggressive B-cell lymphomas: a study of 209 cases. J Clin Pathol. 2016.69(3):266–270.
   PubMed Web of Science ®Google Scholar
• Klapper W, Stoecklein H, Zeynalova S, et al. Structural aberrations affecting the MYC locus indicate a poor prognosis independent of clinical risk factors in diffuse large B-cell lymphomas treated within randomized trials of the German High-Grade Non-Hodgkin’s Lymphoma Study Group (DSHNHL). Leukemia. 2008;22(12):2226–2229.
   PubMed Web of Science ®Google Scholar
• Valera A, López-Guillermo A, Cardesa-Salzmann T, et al. MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica. 2013;98(10):1554–1562.
   PubMed Web of Science ®Google Scholar
• Lu T-X, Fan L, Wang L, et al. MYC or BCL2 copy number aberration is a strong predictor of outcome in patients with diffuse large B-cell lymphoma. Oncotarget. 2015;6(21):18374–18388.
   PubMed Web of Science ®Google Scholar
• Copie-Bergman C, Cuillière-Dartigues P, Baia M, et al. MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study. Blood. 2015;126(22):2466–2474.
   PubMed Web of Science ®Google Scholar
• Campo E. MYC in DLBCL: partners matter. Blood. 2015;126(22):2439–2440.
   PubMed Web of Science ®Google Scholar
• Dunleavy K, Fanale M, LaCasce A, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. Proc Am Soc Hem Meeting. 2014 Abstract 395.
   Google Scholar
• Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360–3365.
   PubMed Web of Science ®Google Scholar
• Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114(17):3533–3537.
   PubMed Web of Science ®Google Scholar
• Dunleavy K, Pittaluga S, Wayne A, et al. MYC + aggressive B-cell lymphomas: novel therapy of untreated Burkitt lymphoma (BL) and MYC + diffuse large B-cell lymphoma (DLBCL) with DA-EPOCH-R. Ann Oncol. 2011;22(Suppl 4): Abstract 71.
   Google Scholar
• Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009;114(11):2273–2279.
   PubMed Web of Science ®Google Scholar
• Li S, Lin P, Fayad LE, et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol. 2012;25(1):145–156.
   PubMed Web of Science ®Google Scholar
• Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis. Blood. 2014;124(15):2354–2361.
   PubMed Web of Science ®Google Scholar
• Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol. 2014;166(6):891–901.
   PubMed Web of Science ®Google Scholar
• Howlett C, Snedecor SJ, Landsburg DJ, et al. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015;170(4):504–514.
   PubMed Web of Science ®Google Scholar
• Clipson A, Barrans S, Zeng N, et al. The prognosis of MYC translocation positive diffuse large B.cell lymphoma depends on the second hit. J Pathol. 2015;1(3):125–133.
   Google Scholar
• Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adults with Burkitt’s lymphoma. N Engl J Med. 2013;369(20):1915–1925.
   PubMed Web of Science ®Google Scholar
• Mead GM, Barrans SL, Qian W, et al. A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood. 2008;112(6):2248–2260.
   PubMed Web of Science ®Google Scholar
• Wilson WH, Jung S-H, Porcu P, et al. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012;97(5):758–765.
   PubMed Web of Science ®Google Scholar
• Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008;26(16):2717–2724.
   PubMed Web of Science ®Google Scholar
• Perry AM, Alvarado-Bernal Y, Laurini JA, et al. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol. 2014;165(3):382–391.
   PubMed Web of Science ®Google Scholar
• Pfeifer M, Grau M, Lenze D, et al. PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proc Natl Acad Sci U S A. 2013;110(30):12420–12425.
   PubMed Web of Science ®Google Scholar
• Gopal AK, Kahl BS, De Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–1018.
   PubMed Web of Science ®Google Scholar
• Tolani B, Gopalakrishnan R, Punj V, et al. Targeting Myc in KSHV-associated primary effusion lymphoma with BET bromodomain inhibitors. Oncogene. 2014 May 29;33(22):2928–2937.
   Google Scholar
• Trabucco SE, Gerstein RM, Evens AM, et al. Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res. 2015 Jan 1;21(1):113–122.
   Google Scholar
• Bhadury J, Nilsson LM, Veppil Muralidharan S, et al. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma. Proc Natl Acad Sci U S A. 2014;111(26):E2721–E2730.
   PubMed Web of Science ®Google Scholar
• Sheth A, Escobar-Alvarez S, Gardner J, et al. Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers. Cell Death Dis. 2014;5:e1152.
   PubMed Web of Science ®Google Scholar
• Jeong SM, Lee A, Lee J, et al. SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J Biol Chem. 2014;289(7):4135–4144.
   PubMed Web of Science ®Google Scholar
• Wilson WH, O’Connor OA, Czuczman MS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11(12):1149–1159.
   PubMed Web of Science ®Google Scholar
• Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–208.
   PubMed Web of Science ®Google Scholar
• Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) at higher cohort doses. Proc ASCO 2014 J Clin Oncol. 2014;32(suppl; abstr 8522):5s.
   Google Scholar
• Choudhary GS, Al-Harbi S, Mazumder S, et al. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015;6:e1593.
   PubMed Web of Science ®Google Scholar
• Cerchietti LC, Ghetu AF, Zhu X, et al. A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. Cancer Cell. 2010;17(4):400–411.
   PubMed Web of Science ®Google Scholar
• Savage KJ, Slack GW, Mottok A, et al. The impact of dual expression of MYC and BCL2 by immunohistochemistry on the risk of CNS relapse in DLBCL. Blood. 2016 May 5;127(18):2182–2188.
   PubMedGoogle Scholar