Frequent upregulation of MYC in plasma cell leukemia.
Plasma cell leukemia (PCL) is a rare form of monoclonal gammopathy, which can originate de novo or evolve from multiple myeloma (MM) as a terminal leukemic phase. Previous cytogenetic studies of PCL have reported the presence of complex karyotypes with involvement of multiple unidentified chromosomal regions. We report here the analysis of 12 PCL (10 primary and two secondary) by metaphase and FISH analysis combined with oligonucleotide array data (244 k, Agilent). Interphase-FISH results were compared with those from a series of 861 newly diagnosed patients with MM. Cytogenetic analysis was successful on 11 patients, all of whom showed clonal chromosomal abnormalities. Compared with MM, t(11;14)(q13;q32) (42% versus 15%; P = 0.027) and t(14;16)(q32;q23) (25% versus 4%; P = 0.010) were more frequent in PCL, although neither the specific partner chromosome involved in the IgH translocation nor the ploidy status predicted for survival. Chromosomes 1, 8, 13, and 16 showed the highest number of copy number alterations with 8q24 being the chromosomal region most frequently involved. In eight of 12 patients we found abnormalities (translocations, one amplification, small deletions, and duplications) that directly targeted or were very close to MYC. Only four of these changes were detected by routine FISH analysis using commercial probes with the others exclusively detected by arrays. Quantitative reverse transcription polymerase chain reaction demonstrated that these different abnormalities were associated with increased levels of MYC mRNA. We conclude that MYC dysregulation by complex mechanisms is one of the major molecular events in the oncogenesis of PCL.
Chiecchio
Laura
L
Leukaemia Research Fund UK Myeloma Forum Cytogenetics Group, Human Genetics Division, University of Southampton, Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wilts, UK. laura.chiecchio@salisbury.nhs.uk
Dagrada
Gian Paolo
GP
White
Helen E
HE
Towsend
Mark R
MR
Protheroe
Rebecca K M
RK
Cheung
Kan Luk
KL
Stockley
David M
DM
Orchard
Kim H
KH
Cross
Nicholas C P
NC
Harrison
Christine J
CJ
Ross
Fiona M
FM
D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007952:Leukemia, Plasma Cell / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018709:Statistics, Nonparametric; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D055815:Young Adult
D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53