Plenary Paper

• Highly recurring mutations are present in WM, including MYD88 L265P, warts, hypogammaglobulinemia, infection, and myelokathexissyndrome–like mutations in CXCR4, and ARID1A. • Small, previously undetected CNAs affecting B-cell regulatory genes are highly prevalent in WM. The genetic basis for Waldenström macroglobulinemia (WM) remains to be clarified. Although 6q losses are commonly present, recurring gene losses in this region remain to be defined. We therefore performed whole genome sequencing (WGS) in 30 WM patients, which included germline/tumor sequencing for 10 patients. Validated somatic mutationsoccurring in >10%of patients includedMYD88,CXCR4, andARID1A that were present in 90%, 27%, and 17% of patients, respectively, and included the activating mutation L265P in MYD88 and warts, hypogammaglobulinemia, infection, and myelokathexis-syndrome–like mutations in CXCR4 that previously have only been described in the germline. WGS also delineated copy number alterations (CNAs) and structural variants in the 10 paired patients. The CXCR4 and CNA findings were validated in independent expansion cohorts of 147 and 30 WM patients, respectively. Validated gene losses due to CNAs involved PRDM2 (93%), BTG1 (87%), HIVEP2 (77%), MKLN1 (77%), PLEKHG1 (70%), LYN (60%), ARID1B (50%), and FOXP1 (37%). Losses in PLEKHG1, HIVEP2, ARID1B, and BCLAF1 constituted the most common deletions within chromosome 6. Although no recurrent translocations were observed, in 2 patients deletions in 6q corresponded with translocation events. These studies evidence highly recurring somatic events, and provide a genomic basis for understanding the pathogenesis of WM. (Blood. 2014;123(11):1637-1646)

[1]  N. Gray,et al.  A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. , 2013, Blood.

[2]  S. Chevret,et al.  Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with Waldenström's macroglobulinemia , 2013, Haematologica.

[3]  M. Cazzola,et al.  Prevalence and clinical significance of the MYD88 (L265P) somatic mutation in Waldenstrom's macroglobulinemia and related lymphoid neoplasms. , 2013, Blood.

[4]  N. Munshi,et al.  MYD88 L265P in Waldenström macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. , 2013, Blood.

[5]  N. Gutiérrez,et al.  MYD88 L265P is a marker highly characteristic of, but not restricted to, Waldenström’s macroglobulinemia , 2013, Leukemia.

[6]  L. Campbell,et al.  ETV6 deletion is a common additional abnormality in patients with myelodysplastic syndromes or acute myeloid leukemia and monosomy 7 , 2012, Haematologica.

[7]  B. Quesnel,et al.  MYD88 L265P mutation in Waldenstrom macroglobulinemia. , 2012, Blood.

[8]  N. Harris,et al.  MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. , 2012, The New England journal of medicine.

[9]  R. Seong,et al.  The SWI/SNF-like BAF Complex Is Essential for Early B Cell Development , 2012, The Journal of Immunology.

[10]  Eric S. Lander,et al.  Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing , 2012, Proceedings of the National Academy of Sciences.

[11]  R. Kuiper,et al.  The Origin and Nature of Tightly Clustered BTG1 Deletions in Precursor B-Cell Acute Lymphoblastic Leukemia Support a Model of Multiclonal Evolution , 2012, PLoS genetics.

[12]  P. Villalonga,et al.  The tumour suppressor FOXO3 is a key regulator of mantle cell lymphoma proliferation and survival , 2012, British journal of haematology.

[13]  T. Tahira,et al.  Genome-wide Repression of NF-κB Target Genes by Transcription Factor MIBP1 and Its Modulation by O-Linked β-N-Acetylglucosamine (O-GlcNAc) Transferase* , 2012, The Journal of Biological Chemistry.

[14]  B. Wood,et al.  The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome. , 2011, Blood.

[15]  S. Pileri,et al.  Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma. , 2011, Blood.

[16]  Tian-Li Wang,et al.  ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. , 2011, Cancer research.

[17]  R. Siebert,et al.  Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma , 2011, Acta Neuropathologica.

[18]  Meng Li,et al.  Somatic Mutations in the Chromatin Remodeling Gene ARID1A Occur in Several Tumor Types , 2011, Human mutation.

[19]  K. Karube,et al.  Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses. , 2011, Blood.

[20]  Steven J. M. Jones,et al.  Frequent mutation of histone modifying genes in non-Hodgkin lymphoma , 2011, Nature.

[21]  Raul Rabadan,et al.  Analysis of the Coding Genome of Diffuse Large B-Cell Lymphoma , 2011, Nature Genetics.

[22]  M. Farrar,et al.  Ebf1 or Pax5 haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia , 2011, The Journal of experimental medicine.

[23]  Michael A McDevitt,et al.  CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia. , 2011, Blood.

[24]  P. Zhang,et al.  Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk , 2011, Nature Immunology.

[25]  Trevor J Pugh,et al.  Initial genome sequencing and analysis of multiple myeloma , 2011, Nature.

[26]  T. Furukawa,et al.  Target genes of the largest human SWI/SNF complex subunit control cell growth. , 2011, The Biochemical journal.

[27]  Joseph M. Connors,et al.  Oncogenically active MYD88 mutations in human lymphoma , 2011, Nature.

[28]  R. Abagyan,et al.  Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists , 2010, Science.

[29]  Mandi M. Murph,et al.  Regulators of G-Protein signaling RGS10 and RGS17 regulate chemoresistance in ovarian cancer cells , 2010, Molecular Cancer.

[30]  N. Koide,et al.  Retinoblastoma Protein-Interacting Zinc Finger 1 (RIZ1) Regulates the Proliferation of Monocytic Leukemia Cells via Activation of p53 , 2010, Cancer investigation.

[31]  Christian Gilissen,et al.  BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia. , 2010, Blood.

[32]  P. Morel,et al.  SDF1/CXCL12 (-801GA) polymorphism is a prognostic factor after treatment initiation in Waldenstrom macroglobulinemia. , 2009, Leukemia research.

[33]  S. Treon How I treat Waldenström macroglobulinemia. , 2009, Blood.

[34]  D. Bernard,et al.  A genetic screen identifies topoisomerase 1 as a regulator of senescence. , 2009, Cancer research.

[35]  J. Carpten,et al.  Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia. , 2009, Cancer research.

[36]  J. Keats,et al.  High-resolution genomic analysis in Waldenström's macroglobulinemia identifies disease-specific and common abnormalities with marginal zone lymphomas. , 2009, Clinical lymphoma & myeloma.

[37]  A. Roccaro,et al.  SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia. , 2008, Blood.

[38]  F. Baleux,et al.  CXCR4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome. , 2008, Blood.

[39]  D. Carrasco,et al.  Targeting NF-kappaB in Waldenstrom macroglobulinemia. , 2008, Blood.

[40]  M. Essafi,et al.  Homeostatic chemokines increase survival of B-chronic lymphocytic leukemia cells through inactivation of transcription factor FOXO3a , 2007, Oncogene.

[41]  J. Christman,et al.  E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury , 2007, Nature Medicine.

[42]  J. Hehir-Kwa,et al.  High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression , 2007, Leukemia.

[43]  Christopher B. Miller,et al.  Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia , 2007, Nature.

[44]  J. Benovic,et al.  Regulation of CXCR4 signaling. , 2007, Biochimica et biophysica acta.

[45]  Xiaomei Wang,et al.  Distinct mammalian SWI/SNF chromatin remodeling complexes with opposing roles in cell‐cycle control , 2007, The EMBO journal.

[46]  Irene Ghobrial,et al.  6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance. , 2006, Cancer genetics and cytogenetics.

[47]  C. Morton,et al.  Characterization of familial Waldenstrom's Macroglobulinemia. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  A. Rossi,et al.  Immunoglobulin M monoclonal gammopathies of undetermined significance and indolent Waldenstrom's macroglobulinemia recognize the same determinants of evolution into symptomatic lymphoid disorders: proposal for a common prognostic scoring system. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  S. Bohlander ETV6: a versatile player in leukemogenesis. , 2005, Seminars in cancer biology.

[50]  Alain Dupuy,et al.  WHIM syndromes with different genetic anomalies are accounted for by impaired CXCR4 desensitization to CXCL12. , 2005, Blood.

[51]  F. Brodsky,et al.  The B Lymphocyte Adaptor Molecule of 32 Kilodaltons (Bam32) Regulates B Cell Antigen Receptor Internalization1 , 2004, The Journal of Immunology.

[52]  S. Gauld,et al.  Src-family kinases in B-cell development and signaling , 2004, Oncogene.

[53]  L. Cavanna,et al.  Clinical characteristics and factors predicting evolution of asymptomatic IgM monoclonal gammopathies and IgM-related disorders , 2004, Leukemia.

[54]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[55]  H. Beug,et al.  FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase 1 , 2004, The Journal of cell biology.

[56]  T. Therneau,et al.  Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. , 2003, Seminars in oncology.

[57]  R. Gorlin,et al.  Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease , 2003, Nature Genetics.

[58]  M. Dimopoulos,et al.  Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. , 2003, Seminars in oncology.

[59]  P. Marynen,et al.  Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumor , 2002, Genes, chromosomes & cancer.

[60]  R. Rabin,et al.  Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein , 2001, Nature Immunology.

[61]  S. Mundell,et al.  Trafficking of the HIV Coreceptor CXCR4 , 1999, The Journal of Biological Chemistry.

[62]  T. Kurosaki,et al.  Syk and Bruton's Tyrosine Kinase Are Required for B Cell Antigen Receptor-mediated Activation of the Kinase Akt* , 1999, The Journal of Biological Chemistry.

[63]  R. Snyderman,et al.  Regulation of Human Chemokine Receptors CXCR4 , 1997, The Journal of Biological Chemistry.

[64]  C. Reynolds,et al.  Frequent loss of heterozygosity at the TEL gene locus in acute lymphoblastic leukemia of childhood. , 1995, Blood.

[65]  M. Ffrench,et al.  BTG1, a member of a new family of antiproliferative genes. , 1992, The EMBO journal.

[66]  E. Cheung,et al.  MYBBP1a is a novel repressor of NF-kappaB. , 2007, Journal of molecular biology.

[67]  T. Wirth,et al.  Bruton's tyrosine kinase is a Toll/interleukin-1 receptor domain-binding protein that participates in nuclear factor kappaB activation by Toll-like receptor 4. , 2003, The Journal of biological chemistry.