Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma.
Two oncogenic pathways have been hypothesized for multiple myeloma (MM) and premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors: a nonhyperdiploid pathway associated with a high prevalence of IgH translocations and a hyperdiploid pathway associated with multiple trisomies of 8 chromosomes. Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity. Translocations can directly dysregulate CCND1 (11q13) or CCND3 (6p21), or MAF (16q23) or MAFB (20q11) transcription factors that target CCND2. Biallelic dysregulation of CCND1 occurs in nearly 40% of tumors, most of which are hyperdiploid. Other tumors express increased CCND2, either with or without a t(4;14) translocation. Using gene expression profiling to identify 5 recurrent translocations, specific trisomies, and expression of cyclin D genes, MM tumors can be divided into 8 TC (translocation/cyclin D) groups (11q13, 6p21, 4p16, maf, D1, D1+D2, D2, and none) that appear to be defined by early, and perhaps initiating, oncogenic events. However, despite subsequent progression events, these groups have differing gene expression profiles and also significant differences in the prevalence of bone disease, frequency at relapse, and progression to extramedullary tumor.
Bergsagel
P Leif
PL
Mayo Clinic Scottsdale, Comprehensive Cancer Center and Division of Hematology-Oncology, Scottsdale, AZ, USA. bergsagel.p@mayo.edu <bergsagel.p@mayo.edu>
Kuehl
W Michael
WM
Zhan
Fenghuang
F
Sawyer
Jeffrey
J
Barlogie
Bart
B
Shaughnessy
John
J
D001847:Bone Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019938:Cyclin D1 / Q000235:genetics*; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins / Q000235:genetics; D020869:Gene Expression Profiling / Q000592:standards; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D015203:Reproducibility of Results; D014178:Translocation, Genetic; D014314:Trisomy
C080336:CCND2 protein, human; C534696:CCND3 protein, human; D056742:Cyclin D2; D056743:Cyclin D3; D016213:Cyclins; D012333:RNA, Messenger; D019938:Cyclin D1