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PMID: 22498740 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Clonal competition with alternating dominance in multiple myeloma.

Blood ·Vol. 120 ·No. 5 ·2012-08-02 ·Pages 1067-76

Keats JJ, Chesi M, Egan JB, Garbitt VM, Palmer SE, Braggio E, Van Wier S, Blackburn PR, Baker AS, Dispenzieri A, Kumar S, Rajkumar SV, Carpten JD, Barrett M, Fonseca R, Stewart AK, Bergsagel PL

Abstract

Emerging evidence indicates that tumors can follow several evolutionary paths over a patient's disease course. With the use of serial genomic analysis of samples collected at different points during the disease course of 28 patients with multiple myeloma, we found that the genomes of standard-risk patients show few changes over time, whereas those of cytogenetically high-risk patients show significantly more changes over time. The results indicate the existence of 3 temporal tumor types, which can either be genetically stable, linearly evolving, or heterogeneous clonal mixtures with shifting predominant clones. A detailed analysis of one high-risk patient sampled at 7 time points over the entire disease course identified 2 competing subclones that alternate in a back and forth manner for dominance with therapy until one clone underwent a dramatic linear evolution. With the use of the Vk*MYC genetically engineered mouse model of myeloma we modeled this competition between subclones for predominance occurring spontaneously and with therapeutic selection.

MeSH Terms
Animals Cells, Cultured Clonal Evolution/genetics,immunology,physiology Cluster Analysis DNA Copy Number Variations/genetics Disease Progression Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, Dominant/physiology Humans Mice Mice, Inbred C57BL Mice, Transgenic Microarray Analysis Models, Biological Multiple Myeloma/genetics,immunology,pathology Recurrence
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Keats Jonathan J
Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, AZ 85259, USA.
Chesi Marta
Egan Jan B
Garbitt Victoria M
Palmer Stephen E
Braggio Esteban
Van Wier Scott
Blackburn Patrick R
Baker Angela S
Dispenzieri Angela
Kumar Shaji
Rajkumar S Vincent
Carpten John D
Barrett Michael
Fonseca Rafael
Stewart A Keith
Bergsagel P Leif
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2012-01-405985
Published
2012-08-02
Epub
2012-00-12
Pages
1067-76
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC3412330
Subset
IM
Grants
NCI NIH HHS · R01 CA136671 · United States
NCI NIH HHS · CA133115 · United States
NIA NIH HHS · R01 AG020686 · United States
NCI NIH HHS · R01 CA133966 · United States
NCI NIH HHS · CA133966 · United States
NCI NIH HHS · CA136671 · United States
NCI NIH HHS · R01 CA083724 · United States
NCI NIH HHS · R01 CA133115 · United States
Databases
GEO
GSE36822, GSE36823, GSE36824, GSE36825
Corrections
CommentIn
PMID: 22592301
CommentIn
PMID: 22859708
External Links
PubMed source DOI: 10.1182/blood-2012-01-405985 PMC Full Text View journal details
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