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Evolutionary biology of high-risk multiple myeloma.

Abstract The outcomes for the majority of patients with myeloma have improved over recent decades, driven by treatment advances. However, there is a subset of patients considered to have high-risk disease who have not benefited. Understanding how high-risk disease evolves from more therapeutically tractable stages is crucial if we are to improve outcomes. This can be accomplished by identifying the genetic mechanisms and mutations driving the transition of a normal plasma cell to one with the features of the following disease stages: monoclonal gammopathy of undetermined significance, smouldering myeloma, myeloma and plasma cell leukaemia. Although myeloma initiating events are clonal, subsequent driver lesions often occur in a subclone of cells, facilitating progression by Darwinian selection processes. Understanding the co-evolution of the clones within their microenvironment will be crucial for therapeutically manipulating the process. The end stage of progression is the generation of a state associated with treatment resistance, increased proliferation, evasion of apoptosis and an ability to grow independently of the bone marrow microenvironment. In this Review, we discuss these end-stage high-risk disease states and how new information is improving our understanding of their evolutionary trajectories, how they may be diagnosed and the biological behaviour that must be addressed if they are to be treated effectively.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title nature reviews. cancer
Publication Year Start




PMID- 28835722
OWN - NLM
STAT- MEDLINE
DA  - 20170824
DCOM- 20170912
LR  - 20170912
IS  - 1474-1768 (Electronic)
IS  - 1474-175X (Linking)
VI  - 17
IP  - 9
DP  - 2017 Aug 24
TI  - Evolutionary biology of high-risk multiple myeloma.
PG  - 543-556
LID - 10.1038/nrc.2017.63 [doi]
AB  - The outcomes for the majority of patients with myeloma have improved over recent 
      decades, driven by treatment advances. However, there is a subset of patients
      considered to have high-risk disease who have not benefited. Understanding how
      high-risk disease evolves from more therapeutically tractable stages is crucial
      if we are to improve outcomes. This can be accomplished by identifying the
      genetic mechanisms and mutations driving the transition of a normal plasma cell
      to one with the features of the following disease stages: monoclonal gammopathy
      of undetermined significance, smouldering myeloma, myeloma and plasma cell
      leukaemia. Although myeloma initiating events are clonal, subsequent driver
      lesions often occur in a subclone of cells, facilitating progression by Darwinian
      selection processes. Understanding the co-evolution of the clones within their
      microenvironment will be crucial for therapeutically manipulating the process.
      The end stage of progression is the generation of a state associated with
      treatment resistance, increased proliferation, evasion of apoptosis and an
      ability to grow independently of the bone marrow microenvironment. In this
      Review, we discuss these end-stage high-risk disease states and how new
      information is improving our understanding of their evolutionary trajectories,
      how they may be diagnosed and the biological behaviour that must be addressed if 
      they are to be treated effectively.
FAU - Pawlyn, Charlotte
AU  - Pawlyn C
AD  - The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.
FAU - Morgan, Gareth J
AU  - Morgan GJ
AD  - The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, 
      Arkansas 72205, USA.
LA  - eng
PT  - Journal Article
PT  - Review
PL  - England
TA  - Nat Rev Cancer
JT  - Nature reviews. Cancer
JID - 101124168
RN  - 0 (Immunoglobulins)
SB  - IM
MH  - Cell Transformation, Neoplastic/*genetics
MH  - DNA Copy Number Variations
MH  - Drug Resistance, Neoplasm/genetics
MH  - Evolution, Molecular
MH  - Humans
MH  - Immunoglobulins/*genetics
MH  - Multiple Myeloma/drug therapy/*genetics
MH  - Mutation
MH  - Plasma Cells/*pathology
MH  - Risk Factors
MH  - Translocation, Genetic
EDAT- 2017/08/25 06:00
MHDA- 2017/09/13 06:00
CRDT- 2017/08/25 06:00
AID - nrc.2017.63 [pii]
AID - 10.1038/nrc.2017.63 [doi]
PST - ppublish
SO  - Nat Rev Cancer. 2017 Aug 24;17(9):543-556. doi: 10.1038/nrc.2017.63.