Monoclonal B-cell lymphocytosis (MBL) is the presence of small B-cell clones in the peripheral blood of healthy subjects. Most MBL have the characteristic phenotype of chronic lymphocyte leukemia (chronic lymphocytic leukemia (CLL)-like MBL), and depending on the number of monoclonal B-cells, may characterize a preclinical stage of the CLL. However, there are also MBL with an atypical (CD5(+) CD20(+/bright) CD23(dim/-) ) or a CD5(neg) phenotype, which remain largely unexplored. We performed an extended immunophenotypic, cytogenetic, and hematologic analysis in 75 CLL-like, 39 atypical, 50 CD5(neg) , and 7 biphenotypic MBL cases to detect differences or similarities among the MBL subsets. The phenotypic analysis showed expression variations in many surface markers and a wide spectrum of disease-specific phenotypes within each MBL subtype. Interphase fluorescent in situ hybridization analysis showed a different panel of aberrations according to the phenotype. Overall, del(13q14) and +12 were the most common abnormalities (39%), whereas del(11q13), del(17p13), and del(6q23) were detected only in 3, 1, and 0 cases, respectively. A comparison of MBL with overt chronic lymphoproliferations revealed common aspects in the preclinical state, regarding both the kind of cytogenetic aberrations detected and the lymphocyte composition. Our findings highlight not only the heterogeneity among MBL subsets but also indicate common biologic features which differentiate MBL from clinical disease.
Previous studies have indicated that periodontal ligament (PDL) cells demonstrate osteogenic potential and osteoblastic differentiation via the extracellular signal-regulated kinase (ERK) pathway under mechanical stress in vitro and in vivo. This study aimed to further analyse this regulatory process experimentally in the rat. The right upper first molars of 25 twelve-week-old male Wistar anaesthetized rats were loaded with forces in order to be moved mesially. Constant forces for 4 hours of 0.25 and 0.5 N were applied in five animals each. Furthermore, constant forces for 2 hours of 0.1 N were applied in 10 animals and afterwards, the first and second molars were permanently separated with composite. In these animals, the antagonists were sliced and five rats were killed after 1 day and five after 2 days. As a last experiment, intermittent forces of 0.1 N and 0.25 Hz were applied in five different animals for 4 hours. The untreated contralateral sides served as the control. Paraffin-embedded sections were analysed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), runt-related transcription factor 2 (Runx2/Cbfa1), and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). Statistical analysis to determine differences between the groups was carried out using a Student's t-test. In selected areas under tension, the proportion of pERK1/2-positive cells was increased compared with those in control teeth under all types of loading, whereas these proportions in selected areas under pressure were increased only after the application of intermittent forces. In representative areas, both under tension and pressure, the proportion of Runx2-positive cells decreased after the application of constant forces. After the application of constant forces for 4 hours in representative areas, both under tension and pressure, the proportion of PCNA-positive cells was lower than those in control teeth. The involvement of pERK1/2, Runx2/cbfa-1, and PCNA in the reaction of PDL cells to different load regimens was verified.
Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia that may appear as de-novo leukemia (pPCL) or on the basis of a pre-existing multiple myeloma (MM), called secondary plasma cell leukemia (sPCL). In this prospective study, we have applied a broad panel of FISH probes in 965 newly diagnosed MM (NDMM) and 44 PCL cases of both types to reveal the particular cytogenetic differences among the three plasma cell dyscrasias. In order to evaluate the frequency and patterns of clonal evolution, the same FISH panel was applied both at diagnosis and at the time of first relapse for 81 relapsed MM patients and both at MM diagnosis and during sPCL transformation for the 19 sPCL cases described here. pPCL was characterized by frequent MYC translocations and t(11;14) with a 11q13 breakpoint centered on the MYEOV gene, not commonly seen in MM. sPCL had a higher number of FISH abnormalities and was strongly associated with the presence of del(17p13), either acquired at the initial MM stage or as a newly acquired lesion upon leukemogenesis in the context of the apparent clonal evolution observed in sPCL. In clinical terms, sPCL showed a shorter overall survival than pPCL with either standard or high-risk (t(4;14) and/or t(14;16) and/or del(17p13) and/or ≥3 concomitant aberrations) abnormalities (median 5 months vs. 21 and 11 months respectively, p < 0.001), suggesting a prognostic stratification based on cytogenetic background. These observations proved relevant in the NDMM setting, where higher levels of circulating plasma cells (CPCs) were strongly associated with high-risk cytogenetics (median frequency of CPCs: 0.11% of peripheral blood nucleated cells for high-risk vs. 0.007% for standard-risk NDMM, p < 0.0001). Most importantly, the combined evaluation of CPCs (higher or lower than a cut-off of 0.03%), together with patients’ cytogenetic status, could be used for an improved prognostic stratification of NDMM patients.
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