Rare Circulating Cells in Familial Waldenström Macroglobulinemia Displaying the MYD88 L265P Mutation Are Enriched by Epstein-Barr Virus Immortalization.
The MYD88 L265P is a recurrent somatic mutation in neoplastic cells from patients with Waldenström Macroglobulinemia (WM). We identified the MYD88 L265P mutation in three individuals from unrelated families, but its presence did not explain the disease segregation within these WM pedigrees. We observed the mutation in these three individuals at high allele fractions in DNA extracted from EBV-immortalized Lymphoblastoid cell lines established from peripheral blood (LCL), but at much lower allele fractions in DNA extracted directly from peripheral blood, suggesting that this mutation is present in a clonal cell subpopulation rather than of germ-line origin. Furthermore, we observed that the MYD88 L265P mutation is enriched in WM families, detected in 40.5% of patients with familial WM or MGUS (10/22 WM, 5/15 MGUS), compared to 3.5% of patients with familial MM or MGUS (0/72 MM, 4/41 MGUS) (p = 10-7). The mutant allele frequency increased with passages in vitro after immortalization with Epstein-Barr virus (EBV) consistent with the MYD88 L265P described gain-of-function proposed for this mutation. The MYD88 L265P mutation appears to be frequently present in circulating cells in patients with WM, and MGUS, and these cells are amenable to immortalization by EBV.
Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
Maroulio
M
Pertesi
Hospices Civils de Lyon, Pierre Bénite, France; INSERM 1052, CNRS 5286, CRCL, Lyon, France; University of Lyon, Lyon, France; ProfilExpert, Lyon, France.
Perrine
P
Galia
ProfilExpert, Lyon, France.
Nicolas
N
Nazaret
Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
Maxime
M
Vallée
INSERM, UMR_S 938, Proliferation and differentiation of stem cells, Paris, France; AP-HP, Hôpital Saint Antoine, Département d'hématologie et de thérapie cellulaire, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, Paris, France.
Laurent
L
Garderet
Service des maladies du sang, Hopital Huriez CHRU, Lille, France; Centre de Recherche INSERM U837, Facteurs de persistance des cellules leucémiques, Institut pour la Recherche sur le Cancer (IRCL), Lille, France.
Xavier
X
Leleu
Unité génomique du myélome, Institut Universitaire du Cancer de Toulouse-Oncopole, CRCT INSERM U1037, Toulouse, France.
Hervé
H
Avet-Loiseau
Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
Matthieu
M
Foll
Biostatistics, International Agency for Research on Cancer, Lyon, France.
Graham
G
Byrnes
ProfilExpert, Lyon, France.
Joel
J
Lachuer
Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
James D
JD
McKay
Hospices Civils de Lyon, Pierre Bénite, France; INSERM 1052, CNRS 5286, CRCL, Lyon, France; University of Lyon, Lyon, France; ProfilExpert, Lyon, France.
Charles
C
Dumontet
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002455:Cell Division; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D005260:Female; D020022:Genetic Predisposition to Disease; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000097:blood / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D017354:Point Mutation; D008258:Waldenstrom Macroglobulinemia / Q000097:blood / Q000235:genetics / Q000473:pathology*
D007075:Immunoglobulin M; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88