ABSTRACT
This review summarises the work-up of patients with monoclonal gammopathy of undetermined significance (MGUS). In persons above 70 years of age, around 5% have MGUS, a premalignant state with a monoclonal plasma immunoglobulin or light chain (M protein) in blood and/or urine. Continuous follow-up is recommended due to a risk of malignant progression of around 1% per year. Immunoglobulin M MGUS primarily progresses to Waldenström's macroglobulinaemia, whereas non-immunoglobulin M MGUS typically progresses to multiple myeloma or amyloid light-chain amyloidosis. Treatment is unnecessary unless in rare cases of severe non-malignant complications. Screening is not advised.
Subject(s)
Immunoglobulin Light-chain Amyloidosis , Monoclonal Gammopathy of Undetermined Significance , Multiple Myeloma , Waldenstrom Macroglobulinemia , Humans , Monoclonal Gammopathy of Undetermined Significance/diagnosis , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/drug therapyABSTRACT
Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide-resistant (-LR) and pomalidomide-resistant (-PR) human myeloma cell lines from two IMiD-sensitive cell lines, OPM2 and NCI-H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4-6 months, until acquirement of stable resistance. By assessing genome-wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD resistance is associated with an increase in genome-wide DNA methylation and an even greater reduction in chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD-resistant cell lines. Moreover, we show that these changes are potentially reversible, as combination of 5-azacytidine and EPZ-6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl transferases and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs.
Subject(s)
DNA Methylation/drug effects , Drug Resistance, Neoplasm/drug effects , Enhancer of Zeste Homolog 2 Protein/metabolism , Lenalidomide/pharmacology , Multiple Myeloma/metabolism , Peptide Hydrolases/metabolism , Thalidomide/analogs & derivatives , Adaptor Proteins, Signal Transducing , Azacitidine/pharmacology , Benzamides/pharmacology , Biphenyl Compounds , Cell Line, Tumor , Chromatin/drug effects , Enhancer of Zeste Homolog 2 Protein/genetics , Gene Expression/drug effects , Gene Expression Profiling , Humans , Morpholines , Multiple Myeloma/drug therapy , Peptide Hydrolases/genetics , Pyridones/pharmacology , Thalidomide/pharmacology , Ubiquitin-Protein LigasesABSTRACT
Invasive mould infections are a major cause of infectious mortality in highly immunosuppressed patients. Incidence in this high risk group is 10-20% with a death rate in excess of 50%. Most invasive moulds are Aspergillus spp. We present a case of a 74-year-old woman with acute lymphoblastic leukaemia who developed a rare disseminated mould infection with Fusarium solani during induction chemotherapy. We present the case story and discuss the pathogenesis, clinical characteristics and treatment of invasive fusariosis.
