Frequent upregulation of MYC in plasma cell leukemia

Abstract

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.

Genome‐wide analysis of primary plasma cell leukemia identifies recurrent imbalances associated with changes in transcriptional profiles

“…4). As regards IGH@ translocations involving MAF gene, we found higher frequency (30.5%) than those reported in previous works, where incidence in pPCL was approximately 10-17% [3,4] if not absent [8], and almost identical to that reported by Chiecchio et al [6]. Finally, we found a 13% incidence of t(4;14), quite similar to an earlier report [3] but different from other studies in which it was found at higher frequency (21-25%) [4,5] or completely absent [6,8].…”

“…Herein, we identified the occurrence of IGH@ translocations in 87% of pPCL cases; such an incidence overlaps with those reported by several authors [3][4][5][6]8], confirming the widely accepted notion that IGH@ translocations are almost an ubiquitous event in PCL. However, the frequency of the different types of partner loci still remains controversial and this is probably related to the heterogeneous series investigated or geographical factors, as already suggested by other Authors [8].…”

“…However, the frequency of the different types of partner loci still remains controversial and this is probably related to the heterogeneous series investigated or geographical factors, as already suggested by other Authors [8]. Specifically, in our study the frequency of the t(11;14) was approximately 40%, quite similar to that reported by some authors [3,6], but lower than that reported by others [5,8]. Overall, the evaluation of Cyclins D in pPCL confirmed the close asso- 14;20) and in one additional case without the evidence of any major IGH@ translocation.…”

“…PPCL can be distinguished from secondary PCL (sPCL) which represents the leukemic transformation of a previously diagnosed multiple myeloma (MM). As described by of t (11;14) and hypodiploidy have been reported [3][4][5][6][7][8]. MYC rearrangements may also occur in pPCL associated with worse clinical outcome [6,8].…”

“…Following this approach, chromosomes 1,6,8,13,14,16, and 17 were the most frequently altered in our series and will be discussed in further details (Supporting Information Fig. 2A-F and Fig.…”