Predictive Biomarkers and Targeted Therapies for Lymphoid Malignancies

  • Raju K. PillaiEmail author
  • Bharat N. Nathwani
  • Lixin Yang


Neoplasms derived from lymphoid cells include precursor lymphoid neoplasms, mature B-cell neoplasms, plasma cell myeloma, mature T- and NK-cell neoplasms, and Hodgkin lymphoma. The morphology and immunophenotype of B-cell neoplasms correlate with various stages of normal B-cell differentiation and are currently used as a basis for their classification and nomenclature. Alterations in the major physiologic pathways in B cells such as the B-cell receptor signaling pathway, T-cell receptor pathway, NF-kB pathway, MAPK pathway, PI3K/AKT1, MTOR pathway, NOTCH signaling pathway, inhibition of apoptosis, impairment of differentiation to plasma cells, and epigenetic alterations play a major role in neoplastic transformation. Advances in understanding of the molecular pathogenesis of lymphomas in recent years, especially using next-generation sequencing, have enabled identification of novel diagnostic, prognostic, and predictive molecular biomarkers. Novel-targeted therapies based on these biomarkers have revolutionized the therapeutic landscape for relapsed and refractory lymphomas.


Diffuse large B-cell lymphoma Follicular lymphoma Burkett lymphoma Mantle cell lymphoma Chronic lymphocytic leukemia Marginal zone lymphoma Lymphoplasmacytic lymphoma Hairy cell leukemia Plasma cell myeloma Lymphoblastic lymphoma Peripheral T-cell lymphoma Adult T-cell leukemia/lymphoma Anaplastic large cell lymphoma Extranodal natural killer/T-cell lymphoma Lymphoblastic lymphoma Hodgkin lymphoma Non-Hodgkin lymphoma 


  1. 1.
    Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri S, Stein H, et al. WHO classification of tumors of hematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2017.Google Scholar
  2. 2.
    Onaindia A, Medeiros LJ, Patel KP. Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms. Mod Pathol Off J U S Can Acad Pathol Inc. 2017;30(10):1338–66. PubMed PMID: 28664939.Google Scholar
  3. 3.
    Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88–92. PubMed PMID: 20054396. Pubmed Central PMCID: 2845535.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lenz G, Davis RE, Ngo VN, Lam L, George TC, Wright GW, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science. 2008;319(5870):1676–9. PubMed PMID: 18323416.CrossRefPubMedGoogle Scholar
  5. 5.
    Love C, Sun Z, Jima D, Li G, Zhang J, Miles R, et al. The genetic landscape of mutations in Burkitt lymphoma. Nat Genet. 2012;44(12):1321–5. PubMed PMID: 23143597. Pubmed Central PMCID: 3674561.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature. 2011;470(7332):115–9. PubMed PMID: 21179087.CrossRefPubMedGoogle Scholar
  7. 7.
    Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet. 2011;43(9):830–7. PubMed PMID: 21804550. Pubmed Central PMCID: 3297422.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, et al. The coding genome of splenic marginal zone lymphoma: activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012;209(9):1537–51. PubMed PMID: 22891273. Pubmed Central PMCID: 3428941. Epub 2012/08/15. eng.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367(9):826–33.CrossRefPubMedGoogle Scholar
  10. 10.
    Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 2009;459(7247):717–21. PubMed PMID: 19412164. Pubmed Central PMCID: 2973325.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Arcaini L, Rossi D. Nuclear factor-kappaB dysregulation in splenic marginal zone lymphoma: new therapeutic opportunities. Haematologica. 2012;97(5):638–40. PubMed PMID: 22556352. Pubmed Central PMCID: 3342963.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rossi D, Fangazio M, Rasi S, Vaisitti T, Monti S, Cresta S, et al. Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood. 2012;119(12):2854–62.CrossRefPubMedGoogle Scholar
  13. 13.
    Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proc Natl Acad Sci U S A. 2012;109(10):3879–84. PubMed PMID: 22343534. Pubmed Central PMCID: 3309757.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010;116(11):1919–23. PubMed PMID: 20519626. Pubmed Central PMCID: 3173987.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Schmitz R, Young RM, Ceribelli M, Jhavar S, Xiao W, Zhang M, et al. Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature. 2012;490(7418):116–20. PubMed PMID: 22885699. Pubmed Central PMCID: 3609867.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Abubaker J, Bavi PP, Al-Harbi S, Siraj AK, Al-Dayel F, Uddin S, et al. PIK3CA mutations are mutually exclusive with PTEN loss in diffuse large B-cell lymphoma. Leukemia. 2007;21(11):2368–70. PubMed PMID: 17657213.CrossRefPubMedGoogle Scholar
  17. 17.
    Rudelius M, Pittaluga S, Nishizuka S, Pham TH, Fend F, Jaffe ES, et al. Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma. Blood. 2006;108(5):1668–76. PubMed PMID: 16645163. Pubmed Central PMCID: 1895501.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    de Miranda NF, Peng R, Georgiou K, Wu C, Falk Sorqvist E, Berglund M, et al. DNA repair genes are selectively mutated in diffuse large B cell lymphomas. J Exp Med. 2013;210(9):1729–42. PubMed PMID: 23960188. Pubmed Central PMCID: 3754869.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mandelbaum J, Bhagat G, Tang H, Mo T, Brahmachary M, Shen Q, et al. BLIMP1 is a tumor suppressor gene frequently disrupted in activated B cell-like diffuse large B cell lymphoma. Cancer Cell. 2010;18(6):568–79. PubMed PMID: 21156281. Pubmed Central PMCID: 3030476.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Chi P, Allis CD, Wang GG. Covalent histone modifications – miswritten, misinterpreted and mis-erased in human cancers. Nat Rev Cancer. 2010;10(7):457–69. PubMed PMID: 20574448. Pubmed Central PMCID: 3262678.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Jiang Y, Melnick A. The epigenetic basis of diffuse large B-cell lymphoma. Semin Hematol. 2015;52(2):86–96. PubMed PMID: 25805588. Pubmed Central PMCID: 4374125.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471(7337):189–95. PubMed PMID: 21390126. Pubmed Central PMCID: 3271441.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Cairns RA, Iqbal J, Lemonnier F, Kucuk C, de Leval L, Jais JP, et al. IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma. Blood. 2012;119(8):1901–3. PubMed PMID: 22215888. Pubmed Central PMCID: 3293643.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rohr J, Guo S, Huo J, Bouska A, Lachel C, Li Y, et al. Recurrent activating mutations of CD28 in peripheral T-cell lymphomas. Leukemia. 2015;5:1062–70.Google Scholar
  25. 25.
    Zeng Y, Feldman AL. Genetics of anaplastic large cell lymphoma. Leuk Lymphoma. 2016;57(1):21–7. PubMed PMID: 26104084.CrossRefPubMedGoogle Scholar
  26. 26.
    Iqbal J, Wright G, Wang C, Rosenwald A, Gascoyne RD, Weisenburger DD, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123(19):2915–23. PubMed PMID: 24632715. Pubmed Central PMCID: PMC4014836. Epub 2014/03/19. eng.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Palomero T, Couronne L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46(2):166–70. PubMed PMID: 24413734. Pubmed Central PMCID: 3963408.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Schatz JH, Horwitz SM, Teruya-Feldstein J, Lunning MA, Viale A, Huberman K, et al. Targeted mutational profiling of peripheral T-cell lymphoma not otherwise specified highlights new mechanisms in a heterogeneous pathogenesis. Leukemia. 2015;29(1):237–41. PubMed PMID: 25257991. Pubmed Central PMCID: 4286477.CrossRefPubMedGoogle Scholar
  29. 29.
    Martin-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B, et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood. 2002;99(4):1474–7. PubMed PMID: 11830502.CrossRefPubMedGoogle Scholar
  30. 30.
    Schmitz R, Stanelle J, Hansmann ML, Kuppers R. Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma. Annu Rev Pathol. 2009;4:151–74. PubMed PMID: 19400691.CrossRefPubMedGoogle Scholar
  31. 31.
    Pillai RK, Chan WC. Pathogenesis of lymphomas. In: Zain J, Kwak L, editors. Management of lymphomas: a case-based approach. Adis, Cham: Springer International Publishing; 2017. p. 11–31.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Raju K. Pillai
    • 1
    Email author
  • Bharat N. Nathwani
    • 1
  • Lixin Yang
    • 1
  1. 1.Department of PathologyCity of Hope National Medical CenterDuarteUSA

Personalised recommendations