title: MYD88 L265P mutation in Waldenstrom macroglobulinemia.
abstract: Mutation of the MYD88 gene has recently been identified in activated B-cell-like diffuse cell lymphoma and enhanced Janus kinase/signal transducer and activator of transcription (JAK-STAT) and nuclear factor κB (NF-κB) signaling pathways. A whole exome-sequencing study of Waldenstrom macroglobulinemia (WM) suggested a high frequency of MYD88 L265P mutation in WM. The genetic background is not fully deciphered in WM, although the role of NF-κB and JAK-STAT has been demonstrated. We analyzed MYD88 mutation in exon 5 and characterized the clinical significance of this genetic alteration in 67 WM patients. Clinical features; immunophenotypic markers; and conventional cytogenetic, fluorescence in situ hybridization, and single nucleotide polymorphism array data were analyzed. MYD88 L265P mutation was acquired in 79% of patients. Overall, we have identified alteration of the MYD88 locus in 91% of WM patients, including 12% with gain on chromosome 3 at the 3p22 locus that included the MYD88 gene. Patients with absence of MYD88 mutation were WM characterized with a female predominance, a splenomegaly, gain of chromosome 3, and CD27 expression. Importantly, inhibition of MYD88 signaling induced cytotoxicity and inhibited cell growth of cell lines issued from patients with WM. In conclusion, these results confirm a high frequency of MYD88 L265P mutation in WM. The discovery of MYD88 L265P mutation may contribute to a better understanding of the physiopathogeny of WM.
authors.affiliation: Department of Hematology-Immunology-Cytogenetic, Centre Hospitalier, Valenciennes, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Poulain
authors.forename: Christophe
authors.initials: C
authors.lastname: Roumier
authors.forename: Audrey
authors.initials: A
authors.lastname: Decambron
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Charles
authors.initials: C
authors.lastname: Herbaux
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bertrand
authors.forename: Sabine
authors.initials: S
authors.lastname: Tricot
authors.forename: Agnès
authors.initials: A
authors.lastname: Daudignon
authors.forename: Sylvie
authors.initials: S
authors.lastname: Galiègue-Zouitina
authors.forename: Valerie
authors.initials: V
authors.lastname: Soenen
authors.forename: Olivier
authors.initials: O
authors.lastname: Theisen
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grardel
authors.forename: Olivier
authors.initials: O
authors.lastname: Nibourel
authors.forename: Catherine
authors.initials: C
authors.lastname: Roche-Lestienne
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.forename: Patrick
authors.initials: P
authors.lastname: Duthilleul
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Xavier
authors.initials: X
authors.lastname: Leleu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction / Q000502:physiology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000378:metabolism; D008258:Waldenstrom Macroglobulinemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy
chemical_list: C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7