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.
High-resolution structures of amyloid fibrils formed from normally-folded proteins have revealed non-native conformations of the polypeptide chains. Attaining these conformations apparently requires ...transition from the native state via a highly disordered conformation, in contrast to earlier models that posited a role for assembly of partially folded proteins. Modifications or interactions that extend the lifetime or constrain the conformations of these disordered states could act to enhance or suppress amyloid formation. Understanding how the properties of both the folded and transiently disordered structural ensembles influence the process of amyloid formation is a substantial challenge, but research into the properties of intrinsically disordered proteins will deliver important insights.
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•High resolution structures of amyloid fibrils have revealed complex, non-native folds.•Individual proteins can form multiple amyloid folds.•Folded proteins aggregate via disordered, rather than native-like intermediate states.•Transiently disordered conformations define the amyloid fold and its interactions.
This article focuses on the interplay between metaphor and metonymy in the construction of organization theory. It emphasizes the importance of understanding the relationship between the use of ...metaphor as a way of thinking and a way of being, and the specific metaphors that are produced through this process. It suggests that too much emphasis is often placed on metaphors as abstracted epistemological constructs rather than on understanding the more dynamic and changing role they play in the interactive modes of engagement through which people seek to grasp, concretize and act on their world. Developing the approach and ideas first presented in Images of Organization, this article suggests that a flexible use of metaphor can help us engage and understand the multidimensional and paradoxical nature of organizational life and help us to deal with the emerging issues shaping the contemporary socio-political–technological–organizational landscape. The article suggests that because most current approaches in social science are overly-focused on the study of abstracted metonymical constructs, they will have difficulty dealing with the multidimensional complexity we now face.
Based on the clinical features of myeloma and related malignancies of plasma cells, it has been possible to generate a model system of myeloma progression from a normal plasma cell through ...smouldering myeloma to myeloma and then plasma cell leukaemia. Using this model system we can study at which points the genetic alterations identified through whole-tumour molecular analyses function in the initiation and progression of myeloma. Further genetic complexity, such as intraclonal heterogeneity, and insights into the molecular evolution and intraclonal dynamics in this model system are crucial to our understandings of tumour progression, treatment resistance and the use of currently available and future treatments.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to ...progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.
The development of next-generation sequencing technology has dramatically improved our understanding of the genetic landscape of multiple myeloma. Several new drivers and recurrent events have been ...reported and linked to a potential driver role. This complex landscape is enhanced by intraclonal mutational heterogeneity and variability introduced through the dimensions of time and space. The evolutionary history of multiple myeloma is driven by both the accumulation of different genomic drivers and by the activity of different mutational processes active overtime. In this review, we describe how these new findings and sequencing technologies have been progressively allowed to understand and reshape our knowledge of the complexity of multiple myeloma at each of its developmental stages: premalignant, at diagnosis, and in relapsed/refractory states. We discuss how these evolutionary concepts can be utilized in the clinic to alter evolutionary trajectories providing a framework for therapeutic intervention at early-disease stages.
Light chain (LC) amyloidosis (AL amyloidosis) appears to be caused by the misfolding, or misfolding and aggregation of an antibody LC or fragment thereof and is fatal if untreated. LCs are secreted ...from clonally expanded plasma cells, generally as disulfide-linked dimers, with each monomer comprising one constant and one variable domain. The energetic contribution of each domain and the role of endoproteolysis in AL amyloidosis remain unclear. To investigate why only some LCs form amyloid and cause organ toxicity, we measured the aggregation propensity and kinetic stability of LC dimers and their associated variable domains from AL amyloidosis patients and non-patients. All the variable domains studied readily form amyloid fibrils, whereas none of the full-length LC dimers, even those from AL amyloidosis patients, are amyloidogenic. Kinetic stability—that is, the free energy difference between the native state and the unfolding transition state—dictates the LC's unfolding rate. Full-length LC dimers derived from AL amyloidosis patients unfold more rapidly than other full-length LC dimers and can be readily cleaved into their component domains by proteases, whereas non-amyloidogenic LC dimers are more kinetically stable and resistant to endoproteolysis. Our data suggest that amyloidogenic LC dimers are kinetically unstable (unfold faster) and are thus susceptible to endoproteolysis that results in the release amyloidogenic LC fragments, whereas other LCs are not as amenable to unfolding and endoproteolysis and are therefore aggregation resistant. Pharmacologic kinetic stabilization of the full-length LC dimer could be a useful strategy to treat AL amyloidosis.
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•Aggregation of antibody LCs is associated with AL amyloidosis.•Full-length LCs are much less amyloidogenic than their variable domains.•LCs from AL amyloidosis patients are less kinetically stable than other LCs.•Amyloidogenesis may be initiated by endoproteolysis of kinetically unstable LCs.•Proteolytic fragments of LCs can form amyloid fibrils.
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