Letters to the Editor
719 C Schaab1,2, FS Oppermann1, M Klammer1, H Pfeifer3, A Tebbe1, T Oellerich3,4,5, J Krauter6, M Levis7, AE Perl8, H Daub1, B Steffen3, K Godl1 and H Serve3,4,5 1 Evotec (Mu¨nchen) GmbH, Am Klopferspitz 19a, Martinsried, Germany; 2 Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, Germany; 3 Department of Medicine, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany; 4 German Cancer Consortium (DKTK), Heidelberg, Germany; 5 German Cancer Research Center (DKFZ), Heidelberg, Germany; 6 Department of Medicine, Hematology/Oncology, Medizinische Hochschule Hannover, Hannover, Germany; 7 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA and 8 Hematologic Malignancies Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA E-mail: [email protected] or [email protected] REFERENCES 1 Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114: 2984–2992. 2 Cortes JE, Perl AE, Dombret H, Kayser S, Steffen B, Rousselot P et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of Quizartinib (AC220) in patientsZ60 years of age with FLT3 ITD positive or negative relapsed/refractory. AML Blood (ASH Ann Meeting Abstr) 2012; 120: Abstract 48. 3 Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 2008; 26: 1367–1372.
4 Klammer M, Dybowksi JN, Hoffmann D, Schaab C. Identification of significant features by a global mean rank test. BMC Bioinfo 2013 (Submitted). 5 Saiki Y, Yamazaki Y, Yoshida M, Katoh O, Nakamura T. Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and downregulated during myeloid differentiation of HL60 cells. Genomics 2000; 70: 387–391. 6 Yin B, Delwel R, Valk PJ, Wallace MR, Loh ML, Shannon KM et al. A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene. Blood 2009; 113: 1075–1085. 7 Dai F, Lin X, Chang C, Feng XH. Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Dev Cell 2009; 16: 345–357. 8 Yoon SO, Shin S, Liu Y, Ballif BA, Woo MS, Gygi SP et al. Ran-binding protein 3 phosphorylation links the Ras and PI3-kinase pathways to nucleocytoplasmic transport. Mol Cell 2008; 29: 362–375. 9 Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD et al. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell 2009; 36: 326–339. 10 Klammer M, Kaminski M, Zedler A, Oppermann F, Blencke S, Marx S et al. Phosphosignature predicts dasatinib response in non-small cell lung cancer. Mol Cell proteomics 2012; 11: 651–668. 11 Gakovic M, Shu X, Kasioulis I, Carpanini S, Moraga I, Wright AF. The role of RPGR in cilia formation and actin stability. Hum mol genet 2011; 20: 4840–4850. 12 Meier R, Muller PR, Hirt A, Leibundgut K, Ridolfi-Luthy A, Wagner HP. Differential phosphorylation of lamin B2 in normal and leukemic cells. Leuk Res 1997; 21: 841–847. 13 Kitteringham NR, Jenkins RE, Lane CS, Elliott VL, Park BK. Multiple reaction monitoring for quantitative biomarker analysis in proteomics and metabolomics. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 1229–1239.
This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http:// creativecommons.org/licenses/by/3.0/
Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)
High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma Leukemia (2014) 28, 719–720; doi:10.1038/leu.2013.348
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous class of lymphomas, comprising of molecularly distinct subtypes that differ in gene-expression profile (GEP), genetic aberrations, clinical presentation and disease outcome.1,2 Within this lymphoma class, primary testicular lymphoma (PTL) is a distinctive entity characterized by unique clinical and molecular features, including its exclusive manifestation in the immune-privileged microenvironment of the testis and frequent dissemination to the contralateral testis and the central nervous system (CNS).3,4 Although the incidence of PTL has significantly increased over the last decades, there is at present no consensus on a standard therapeutic regimen.3,4 A current GEP-based molecular classification of DLBCL distinguishes two main subtypes: activated B-cell-like (ABC) lymphoma and germinal-center B-celllike lymphoma.1 PTLs belong to the ABC-DLBCL subtype that is characterized by constitutively active nuclear factor (NF)-kB signaling.1,2 NF-kB pathway activation in DLBCL may result from oncogenic CARD11 mutations and/or of CD79 mutations causing chronic active B-cell receptor (BCR) signaling.5–7 In addition, somatically acquired mutations in MYD88, an adaptor protein that mediates toll-like receptor (TLR) and interleukin-1 receptor
signaling were shown to promote NF-kB and JAK-STAT3 signaling in this lymphoma type.8 Intriguingly, recent studies indicate that the prevalence of oncogenic MYD88 mutations varies greatly among the ABC–DLBCL presenting at different anatomical sites: whereas MYD88 mutations show a high prevalence in primary-CNS-lymphomas (PCNSLs) as well as in lymphomas arising at some other extra-nodal sites, they are relatively uncommon in primary nodal and gastro-intestinal DLBCL.9–11 In a survey of genomic alterations in a large panel of DLBCL, we recently found an activating MYD88 mutation in 10 out of 14 PTLs studied,11 suggesting a high mutation prevalence. Here we extended these series to obtain robust evidence for a role of deregulated MYD88 signaling in PTLs. The study material comprised a panel of 37 PTL diagnosed as DLBCLs according the World Health Organization classification, 14 of which have been reported previously.11 All tumors were extensively immuno-phenotyped, including antibodies against CD20, CD10, MUM1, BCL-2 and BCL-6, and tested for Epstein–Barr virus (EBV) expression by EBV-encoded RNA in-situ hybridization, and tested for translocations of BCL-2, BCL-6 and c-MYC by fluorescence in-situ hybridization (Supplementary Table 1).11 To detect somatic mutations in MYD88 and CD79B, a panel of allele-specific PCRs covering all major mutation (hot) spots8 was employed. As recently reported, this strategy permits efficient and sensitive detection of mutations using DNA extracted from the
Accepted article preview online 20 November 2013; advance online publication, 13 December 2013
& 2014 Macmillan Publishers Limited
Leukemia (2014) 694 – 725
Letters to the Editor
720 paraffin-embedded tissue, even in samples with relatively low tumor load.11 The detected mutations were verified by Sanger sequencing. Of the 37 PTLs studied, 25 tumors (68%) were found to harbor a MYD88 mutation (Supplementary Table 1). All these mutations concerned a leucine to proline exchange at position 265 (L265P). Among other MYD88 mutations reported, the L265P mutant has been shown to be biologically the most potent and was unique in its ability to organize a stable signaling complex containing phosphorylated IRAK1.8 These characteristics presumably explain its ‘hotspot’ status in lymphomas, including DLBCL and Waldenstro¨ms macroglobulinemia.8,12 A CD79B mutation was found in 7 of the 37 PTLs (Supplementary Table 1). Interestingly, these tumors all harbored a coexisting MYD88 mutation. Our finding that MYD88 mutations are highly prevalent in PTLs confirm and extend previous studies reporting a remarkable site-specific variation in the prevalence of MYD88 mutations. Although MYD88 mutations were relatively infrequent in ABC DLBCLs arising in lymph nodes or gut, tumors arising outside these ‘professional’ lymphoid tissues frequently contained MYD88 mutations, either with or without a coexisting CD79B mutation. Interestingly, they were found to be present in up to 75% of PCNSLs, which together with testicular lymphomas represent the immune-privileged site-associated diffuse large B cell lymphomas (IP-DLBCL). Our current finding of a prevalence of MYD88 mutation in PTL that is comparable to that reported for PCNSLs9–11 supports the concept that IP-DLBCLs present a molecularly distinct group of lymphomas with shared pathogenetic features. Conceivably, mutational activation of TLR/MYD88 signaling may endow lymphoma-initiating cells with a selective growth advantage at immune-privileged sites. Other than lymph nodes and mucosa-associated lymphoid tissues, IP-sites are barrier-protected and immunologically silent and, consequently, will likely under normal circumstances provide only limited stimulation by TLR ligands. Coexistent CD79B (or other BCR pathway) mutations, causing chronic active BCR signaling, may further promote the selective outgrowth of the tumor cells within the stimulus-low IP microenvironment. In view of the crucial role of adhesion and chemokine receptors in tissuespecific lymphoma dissemination,13,14 dysregulated ‘homing’ of lymphoma cells carrying oncogenic MYD88 and/or CD79 mutations could present an alternative mechanism underlying the observed site-specific differences in prevalence of these mutations in DLBCL.13 In conclusion, our results suggest that MYD88 mutations, and to a lesser extent CD79B mutations, are important drivers of lymphomagenesis in PTL. Presumably, PTL patients may benefit from therapies targeting MYD88 signaling components, including IRAK kinase inhibitors, either alone or in combination with drugs blocking key mediators of BCR signaling such as Bruton’s tyrosine kinase.14,15 It will be of interest to explore if patients with DLBCLs arising in lymph nodes and MALT and lacking these mutations, nevertheless also show evidence of active MYD88 and/or BCR signaling. Such activation might be triggered by environmental ligands and be associated with non-oncogene addiction to these pathways. Thus, like PTL patients, these patients may also benefit from therapy targeting MYD88 and/or BCR signaling.
CONFLICT OF INTEREST The authors declare no conflict of interest.
W Kraan1, M van Keimpema1, HM Horlings1, EJM Schilder-Tol1, MECM Oud1, LA Noorduyn2, PM Kluin3, MJ Kersten4, M Spaargaren1,5 and ST Pals1,5 1 Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Pathology Laboratory, Dordrecht, The Netherlands; 3 Department of Pathology, University Medical Center, Groningen, The Netherlands and 4 Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands E-mail: [email protected] 5 These authors share last authorship. REFERENCES 1 Shaffer 3rd Al, Young RM, Staudt LM. The biology of human lymphoid malignancies revealed by gene expression profiling. Ann Rev Immunol 2012; 30: 565–610. 2 Pasqualucci L. The genetic basis of diffuse large B-cell lymphoma. Curr Opin Hemmatol 2013; 20: 336–344. 3 Ahmad SS, Idris SF, Follows GA, Williams MV. Primary testicular lymphoma. Clin Oncol 2012; 24: 358–365. 4 Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximabCHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 2011; 29: 2766–2772. 5 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: 1676–1679. 6 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: 717–721. 7 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: 88–92. 8 Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470: 115–119. 9 Gonzalez-Aguilar A, Idbaih A, Boisselier B, Habbita N, Rossetto M, Laurenge A et al. Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res 2012; 18: 5203–5211. 10 Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M. Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol 2011; 122: 791–792. 11 Kraan W, Horlings HM, van Keimpema M, Schilder-Tol EJM, Oud MECM, Scheepstra C et al. High prevalence of oncogenic MYD88 and CD79B mutations in diffuse large B-cell lymphomas presenting at immuneprivileged sites. Blood Cancer J 2013; 3: e139. 12 Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y et al. MYD88 L265P somatic mutation in Waldenstro¨m’s macroglobulinemia. N Engl J Med 2012; 367: 826–833. 13 Pals ST, de Gorter DJ, Spaargaren M. Lymphoma dissemination: the other face of lymphocyte homing. Blood 2007; 110: 3102–3111. 14 de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012; 119: 2590–2594. 15 Lim KH, Romero DL, Chaudhary D, Robinson SD, Staudt LM. IRAK4 kinase as a novel therapeutic target in the abc subtype of diffuse large B cell lymphoma. ASH Annual Meeting Abstracts 2012; 120: 62.
Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)
Leukemia (2014) 694 – 725
& 2014 Macmillan Publishers Limited
719 C Schaab1,2, FS Oppermann1, M Klammer1, H Pfeifer3, A Tebbe1, T Oellerich3,4,5, J Krauter6, M Levis7, AE Perl8, H Daub1, B Steffen3, K Godl1 and H Serve3,4,5 1 Evotec (Mu¨nchen) GmbH, Am Klopferspitz 19a, Martinsried, Germany; 2 Max Planck Institute of Biochemistry, Am Klopferspitz 18, Martinsried, Germany; 3 Department of Medicine, Hematology/Oncology, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany; 4 German Cancer Consortium (DKTK), Heidelberg, Germany; 5 German Cancer Research Center (DKFZ), Heidelberg, Germany; 6 Department of Medicine, Hematology/Oncology, Medizinische Hochschule Hannover, Hannover, Germany; 7 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA and 8 Hematologic Malignancies Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA E-mail: [email protected] or [email protected] REFERENCES 1 Zarrinkar PP, Gunawardane RN, Cramer MD, Gardner MF, Brigham D, Belli B et al. AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML). Blood 2009; 114: 2984–2992. 2 Cortes JE, Perl AE, Dombret H, Kayser S, Steffen B, Rousselot P et al. Final results of a phase 2 open-label, monotherapy efficacy and safety study of Quizartinib (AC220) in patientsZ60 years of age with FLT3 ITD positive or negative relapsed/refractory. AML Blood (ASH Ann Meeting Abstr) 2012; 120: Abstract 48. 3 Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 2008; 26: 1367–1372.
4 Klammer M, Dybowksi JN, Hoffmann D, Schaab C. Identification of significant features by a global mean rank test. BMC Bioinfo 2013 (Submitted). 5 Saiki Y, Yamazaki Y, Yoshida M, Katoh O, Nakamura T. Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and downregulated during myeloid differentiation of HL60 cells. Genomics 2000; 70: 387–391. 6 Yin B, Delwel R, Valk PJ, Wallace MR, Loh ML, Shannon KM et al. A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene. Blood 2009; 113: 1075–1085. 7 Dai F, Lin X, Chang C, Feng XH. Nuclear export of Smad2 and Smad3 by RanBP3 facilitates termination of TGF-beta signaling. Dev Cell 2009; 16: 345–357. 8 Yoon SO, Shin S, Liu Y, Ballif BA, Woo MS, Gygi SP et al. Ran-binding protein 3 phosphorylation links the Ras and PI3-kinase pathways to nucleocytoplasmic transport. Mol Cell 2008; 29: 362–375. 9 Choudhary C, Olsen JV, Brandts C, Cox J, Reddy PN, Bohmer FD et al. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes. Mol Cell 2009; 36: 326–339. 10 Klammer M, Kaminski M, Zedler A, Oppermann F, Blencke S, Marx S et al. Phosphosignature predicts dasatinib response in non-small cell lung cancer. Mol Cell proteomics 2012; 11: 651–668. 11 Gakovic M, Shu X, Kasioulis I, Carpanini S, Moraga I, Wright AF. The role of RPGR in cilia formation and actin stability. Hum mol genet 2011; 20: 4840–4850. 12 Meier R, Muller PR, Hirt A, Leibundgut K, Ridolfi-Luthy A, Wagner HP. Differential phosphorylation of lamin B2 in normal and leukemic cells. Leuk Res 1997; 21: 841–847. 13 Kitteringham NR, Jenkins RE, Lane CS, Elliott VL, Park BK. Multiple reaction monitoring for quantitative biomarker analysis in proteomics and metabolomics. J Chromatogr B Analyt Technol Biomed Life Sci 2009; 877: 1229–1239.
This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http:// creativecommons.org/licenses/by/3.0/
Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)
High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma Leukemia (2014) 28, 719–720; doi:10.1038/leu.2013.348
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous class of lymphomas, comprising of molecularly distinct subtypes that differ in gene-expression profile (GEP), genetic aberrations, clinical presentation and disease outcome.1,2 Within this lymphoma class, primary testicular lymphoma (PTL) is a distinctive entity characterized by unique clinical and molecular features, including its exclusive manifestation in the immune-privileged microenvironment of the testis and frequent dissemination to the contralateral testis and the central nervous system (CNS).3,4 Although the incidence of PTL has significantly increased over the last decades, there is at present no consensus on a standard therapeutic regimen.3,4 A current GEP-based molecular classification of DLBCL distinguishes two main subtypes: activated B-cell-like (ABC) lymphoma and germinal-center B-celllike lymphoma.1 PTLs belong to the ABC-DLBCL subtype that is characterized by constitutively active nuclear factor (NF)-kB signaling.1,2 NF-kB pathway activation in DLBCL may result from oncogenic CARD11 mutations and/or of CD79 mutations causing chronic active B-cell receptor (BCR) signaling.5–7 In addition, somatically acquired mutations in MYD88, an adaptor protein that mediates toll-like receptor (TLR) and interleukin-1 receptor
signaling were shown to promote NF-kB and JAK-STAT3 signaling in this lymphoma type.8 Intriguingly, recent studies indicate that the prevalence of oncogenic MYD88 mutations varies greatly among the ABC–DLBCL presenting at different anatomical sites: whereas MYD88 mutations show a high prevalence in primary-CNS-lymphomas (PCNSLs) as well as in lymphomas arising at some other extra-nodal sites, they are relatively uncommon in primary nodal and gastro-intestinal DLBCL.9–11 In a survey of genomic alterations in a large panel of DLBCL, we recently found an activating MYD88 mutation in 10 out of 14 PTLs studied,11 suggesting a high mutation prevalence. Here we extended these series to obtain robust evidence for a role of deregulated MYD88 signaling in PTLs. The study material comprised a panel of 37 PTL diagnosed as DLBCLs according the World Health Organization classification, 14 of which have been reported previously.11 All tumors were extensively immuno-phenotyped, including antibodies against CD20, CD10, MUM1, BCL-2 and BCL-6, and tested for Epstein–Barr virus (EBV) expression by EBV-encoded RNA in-situ hybridization, and tested for translocations of BCL-2, BCL-6 and c-MYC by fluorescence in-situ hybridization (Supplementary Table 1).11 To detect somatic mutations in MYD88 and CD79B, a panel of allele-specific PCRs covering all major mutation (hot) spots8 was employed. As recently reported, this strategy permits efficient and sensitive detection of mutations using DNA extracted from the
Accepted article preview online 20 November 2013; advance online publication, 13 December 2013
& 2014 Macmillan Publishers Limited
Leukemia (2014) 694 – 725
Letters to the Editor
720 paraffin-embedded tissue, even in samples with relatively low tumor load.11 The detected mutations were verified by Sanger sequencing. Of the 37 PTLs studied, 25 tumors (68%) were found to harbor a MYD88 mutation (Supplementary Table 1). All these mutations concerned a leucine to proline exchange at position 265 (L265P). Among other MYD88 mutations reported, the L265P mutant has been shown to be biologically the most potent and was unique in its ability to organize a stable signaling complex containing phosphorylated IRAK1.8 These characteristics presumably explain its ‘hotspot’ status in lymphomas, including DLBCL and Waldenstro¨ms macroglobulinemia.8,12 A CD79B mutation was found in 7 of the 37 PTLs (Supplementary Table 1). Interestingly, these tumors all harbored a coexisting MYD88 mutation. Our finding that MYD88 mutations are highly prevalent in PTLs confirm and extend previous studies reporting a remarkable site-specific variation in the prevalence of MYD88 mutations. Although MYD88 mutations were relatively infrequent in ABC DLBCLs arising in lymph nodes or gut, tumors arising outside these ‘professional’ lymphoid tissues frequently contained MYD88 mutations, either with or without a coexisting CD79B mutation. Interestingly, they were found to be present in up to 75% of PCNSLs, which together with testicular lymphomas represent the immune-privileged site-associated diffuse large B cell lymphomas (IP-DLBCL). Our current finding of a prevalence of MYD88 mutation in PTL that is comparable to that reported for PCNSLs9–11 supports the concept that IP-DLBCLs present a molecularly distinct group of lymphomas with shared pathogenetic features. Conceivably, mutational activation of TLR/MYD88 signaling may endow lymphoma-initiating cells with a selective growth advantage at immune-privileged sites. Other than lymph nodes and mucosa-associated lymphoid tissues, IP-sites are barrier-protected and immunologically silent and, consequently, will likely under normal circumstances provide only limited stimulation by TLR ligands. Coexistent CD79B (or other BCR pathway) mutations, causing chronic active BCR signaling, may further promote the selective outgrowth of the tumor cells within the stimulus-low IP microenvironment. In view of the crucial role of adhesion and chemokine receptors in tissuespecific lymphoma dissemination,13,14 dysregulated ‘homing’ of lymphoma cells carrying oncogenic MYD88 and/or CD79 mutations could present an alternative mechanism underlying the observed site-specific differences in prevalence of these mutations in DLBCL.13 In conclusion, our results suggest that MYD88 mutations, and to a lesser extent CD79B mutations, are important drivers of lymphomagenesis in PTL. Presumably, PTL patients may benefit from therapies targeting MYD88 signaling components, including IRAK kinase inhibitors, either alone or in combination with drugs blocking key mediators of BCR signaling such as Bruton’s tyrosine kinase.14,15 It will be of interest to explore if patients with DLBCLs arising in lymph nodes and MALT and lacking these mutations, nevertheless also show evidence of active MYD88 and/or BCR signaling. Such activation might be triggered by environmental ligands and be associated with non-oncogene addiction to these pathways. Thus, like PTL patients, these patients may also benefit from therapy targeting MYD88 and/or BCR signaling.
CONFLICT OF INTEREST The authors declare no conflict of interest.
W Kraan1, M van Keimpema1, HM Horlings1, EJM Schilder-Tol1, MECM Oud1, LA Noorduyn2, PM Kluin3, MJ Kersten4, M Spaargaren1,5 and ST Pals1,5 1 Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Pathology Laboratory, Dordrecht, The Netherlands; 3 Department of Pathology, University Medical Center, Groningen, The Netherlands and 4 Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands E-mail: [email protected] 5 These authors share last authorship. REFERENCES 1 Shaffer 3rd Al, Young RM, Staudt LM. The biology of human lymphoid malignancies revealed by gene expression profiling. Ann Rev Immunol 2012; 30: 565–610. 2 Pasqualucci L. The genetic basis of diffuse large B-cell lymphoma. Curr Opin Hemmatol 2013; 20: 336–344. 3 Ahmad SS, Idris SF, Follows GA, Williams MV. Primary testicular lymphoma. Clin Oncol 2012; 24: 358–365. 4 Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximabCHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 2011; 29: 2766–2772. 5 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: 1676–1679. 6 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: 717–721. 7 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: 88–92. 8 Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470: 115–119. 9 Gonzalez-Aguilar A, Idbaih A, Boisselier B, Habbita N, Rossetto M, Laurenge A et al. Recurrent mutations of MYD88 and TBL1XR1 in primary central nervous system lymphomas. Clin Cancer Res 2012; 18: 5203–5211. 10 Montesinos-Rongen M, Godlewska E, Brunn A, Wiestler OD, Siebert R, Deckert M. Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma. Acta Neuropathol 2011; 122: 791–792. 11 Kraan W, Horlings HM, van Keimpema M, Schilder-Tol EJM, Oud MECM, Scheepstra C et al. High prevalence of oncogenic MYD88 and CD79B mutations in diffuse large B-cell lymphomas presenting at immuneprivileged sites. Blood Cancer J 2013; 3: e139. 12 Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y et al. MYD88 L265P somatic mutation in Waldenstro¨m’s macroglobulinemia. N Engl J Med 2012; 367: 826–833. 13 Pals ST, de Gorter DJ, Spaargaren M. Lymphoma dissemination: the other face of lymphocyte homing. Blood 2007; 110: 3102–3111. 14 de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood 2012; 119: 2590–2594. 15 Lim KH, Romero DL, Chaudhary D, Robinson SD, Staudt LM. IRAK4 kinase as a novel therapeutic target in the abc subtype of diffuse large B cell lymphoma. ASH Annual Meeting Abstracts 2012; 120: 62.
Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)
Leukemia (2014) 694 – 725
& 2014 Macmillan Publishers Limited
