Mechanisms and clinical applications of chromosomal instability in lymphoid malignancy
Corresponding Author
Maxwell M. Krem
Department of Medicine and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Correspondence: Maxwell M. Krem, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
E-mail: [email protected]
Search for more papers by this authorOliver W. Press
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Search for more papers by this authorMarshall S. Horwitz
Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA
Search for more papers by this authorTimothy Tidwell
Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA
Search for more papers by this authorCorresponding Author
Maxwell M. Krem
Department of Medicine and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Correspondence: Maxwell M. Krem, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
E-mail: [email protected]
Search for more papers by this authorOliver W. Press
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Search for more papers by this authorMarshall S. Horwitz
Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA
Search for more papers by this authorTimothy Tidwell
Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, USA
Search for more papers by this authorSummary
Lymphocytes are unique among cells in that they undergo programmed DNA breaks and translocations, but that special property predisposes them to chromosomal instability (CIN), a cardinal feature of neoplastic lymphoid cells that manifests as whole chromosome- or translocation-based aneuploidy. In several lymphoid malignancies translocations may be the defining or diagnostic markers of the diseases. CIN is a cornerstone of the mutational architecture supporting lymphoid neoplasia, though it is perhaps one of the least understood components of malignant transformation in terms of its molecular mechanisms. CIN is associated with prognosis and response to treatment, making it a key area for impacting treatment outcomes and predicting prognoses. Here we will review the types and mechanisms of CIN found in Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma and the lymphoid leukaemias, with emphasis placed on pathogenic mutations affecting DNA recombination, replication and repair; telomere function; and mitotic regulation of spindle attachment, centrosome function, and chromosomal segregation. We will discuss the means by which chromosome-level genetic aberrations may give rise to multiple pathogenic mutations required for carcinogenesis and conclude with a discussion of the clinical applications of CIN and aneuploidy to diagnosis, prognosis and therapy.
Supporting Information
Filename | Description |
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bjh13507-sup-0001-Supinfo.docWord document, 171 KB | Table SI. Murine lymphoma models based on aberrant DNA replication. Table SII. Murine lymphoma knockout models based on deficient NHEJ in V(D)J recombination and DSB repair. Table SIII. Dysregulated murine genes requiring concomitant p53 knockout for lymphoma phenotype. Myc and Bax are upregulated; all other models result from losses of function. Table SIV. Disease-specific cytogenetic associations. The table includes clinically notable associations and breakpoints, and for practical purposes it cannot be exhaustive. Table SV. Human genes linked to CIN in lymphoid malignancies. Table SVI. Relevant citations for novel therapeutics exploiting CIN in lymphoid cancers. ATL, HTLV-1-induced adult T cell leukemia-lymphoma; HSP90, heat shock protein 90; KSP, kinesin spindle protein; Ph-ALL, Philadelphia chromosome-positive ALL; PR, partial response; SD, stable disease. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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