title: Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma.
abstract: To elucidate the mechanisms underlying relapse from chemotherapy in multiple myeloma, we performed a longitudinal study of 33 patients entered into Total Therapy protocols investigating them using gene expression profiling, high-resolution copy number arrays, and whole-exome sequencing. The study illustrates the mechanistic importance of acquired mutations in known myeloma driver genes and the critical nature of biallelic inactivation events affecting tumor suppressor genes, especially TP53, the end result being resistance to apoptosis and increased proliferation rates, which drive relapse by Darwinian-type clonal evolution. The number of copy number aberration changes and biallelic inactivation of tumor suppressor genes was increased in GEP70 high risk, consistent with genomic instability being a key feature of high risk. In conclusion, the study highlights the impact of acquired genetic events, which enhance the evolutionary fitness level of myeloma-propagating cells to survive multiagent chemotherapy and to result in relapse.
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Niels
authors: N
authors: Weinhold
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Cody
authors: C
authors: Ashby
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Leo
authors: L
authors: Rasche
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Shweta S
authors: SS
authors: Chavan
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Caleb
authors: C
authors: Stein
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Owen W
authors: OW
authors: Stephens
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Ruslana
authors: R
authors: Tytarenko
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Michael A
authors: MA
authors: Bauer
authors: Department of Molecular and Experimental Medicine, Avera Cancer Institute, La Jolla, CA.
authors: Tobias
authors: T
authors: Meissner
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Shayu
authors: S
authors: Deshpande
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Purvi H
authors: PH
authors: Patel
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Timea
authors: T
authors: Buzder
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Gabor
authors: G
authors: Molnar
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Erich A
authors: EA
authors: Peterson
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Frits
authors: F
authors: van Rhee
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Maurizio
authors: M
authors: Zangari
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Sharmilan
authors: S
authors: Thanendrarajan
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Carolina
authors: C
authors: Schinke
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Erming
authors: E
authors: Tian
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Joshua
authors: J
authors: Epstein
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Bart
authors: B
authors: Barlogie
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Faith E
authors: FE
authors: Davies
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Christoph J
authors: CJ
authors: Heuck
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Brian A
authors: BA
authors: Walker
authors: Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR; and.
authors: Gareth J
authors: GJ
authors: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D060965:Clonal Evolution; D056915:DNA Copy Number Variations; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D011905:Genes, ras; D042822:Genomic Instability; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012008:Recurrence; D012307:Risk Factors; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous
chemical_list: D019869:Phosphatidylinositol 3-Kinases