Quantitative Superresolution Microscopy Reveals Differences in Nuclear DNA Organization of Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

Abstract

The mammalian nucleus has a distinct substructure that cannot be visualized directly by conventional microscopy. In this study, the organization of the DNA within the nucleus of multiple myeloma (MM) cells, their precursor cells (monoclonal gammopathy of undetermined significance; MGUS) and control lymphocytes of the representative patients is visualized and quantified by superresolution microscopy. Three‐dimensional structured illumination microscopy (3D‐SIM) increases the spatial resolution beyond the limits of conventional widefield fluorescence microscopy. 3D‐SIM reveals new insights into the nuclear architecture of cancer as we show for the first time that it resolves organizational differences in intranuclear DNA organization of myeloma cells in MGUS and in MM patients. In addition, we report a significant increase in nuclear submicron DNA structure and structure of the DNA‐free space in myeloma nuclei compared to normal lymphocyte nuclei. Our study provides previously unknown details of the nanoscopic DNA architecture of interphase nuclei of the normal lymphocytes, MGUS and MM cells. This study opens new avenues to understanding the disease progression from MGUS to MM. J. Cell. Biochem. 116: 704–710, 2015. © 2014 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals, Inc.

Distinct and shared three‐dimensional chromosome organization patterns in lymphocytes, monoclonal gammopathy of undetermined significance and multiple myeloma

“…Among myeloma nuclei, the nuclear volume of MM nuclei and MGUS nuclei was not significantly different ( p = 0.215). These results supported our previous findings demonstrating increased nuclear volumes in myeloma nuclei . Correspondingly, the absolute CT volumes in myeloma nuclei were also larger than in control lymphocytes (Fig.…”

DNA Superresolution Structure of Reed–Sternberg Cells Differs Between Long‐Lasting Remission Versus Relapsing Hodgkin's Lymphoma Patients

“…The changes to the DNA structure and the structure of the DNA‐free space might, therefore, be different for different cancers as well, if existent at all. Changes in this structure have, however, also been observed in multiple myeloma [Sathitruangsak et al, ]. Further studies could show how general these changes are in cancer and whether the severity of these changes has predictive value in disease outcomes.…”

The three‐dimensional cancer nucleus

“…In the cancer cell nucleus, the DNA organization assumes an altered pattern, in which the DNA‐poor spaces (interchromatin spaces) and circular DNA‐poor spaces (distinct from nucleoli) increase (Figure A). Measurements of the DNA‐containing and DNA‐poor spaces indicated a significant increase in DNA‐poor spaces in multiple myeloma and in Hodgkin's lymphoma (HL) . Interestingly, there is an increase in DNA‐poor spaces from normal, to premalignant, to malignant cells as shown for normal lymphocytes, monoclonal gammopathy of undetermined significance, and multiple myeloma, respectively (Figure B).…”