Biomedical subjects

Dirk Hose

Publications and source records attributed to Dirk Hose.

10 recordsLinked to original sources

PubMed2026

Myeloma engraftment suppresses osteocytic ossification signatures rescued by loading in mice and reveals predictors of patient outcome.

Multiple myeloma (MM) is a malignant plasma cell disease inducing osteolytic lesions by disrupting bone homeostasis, fostering catabolic and suppressing anabolic functions. While the impact on osteoblast generation and function is well documented, alterations of osteocyte function and extracellular matrix (ECM) are not yet fully understood. Thus, using a syngeneic mouse model of MM by injecting MOPC315.BM cells intratibially into BALB/c mice (n = 95), we performed transcriptomic profiling of an osteocyte-enriched population and identified a mechanosensitive matrisomal gene signature, which was disrupted by tumor engraftment. Non-invasive tibial loading restored the expression of 94 ECM-associated genes, including collagens, fibronectin, and aggrecan. Cross-species integration with RNA-seq data from 387 MM patients revealed eight ECM-related genes whose expression correlated with overall survival (VEGFA, BCAN, FGF13, TNFSF8, SDC1, LAMC1, SEMA3A, and CCL2). Four of these genes (Vegfa, Sdc1, Sema3a, Ccl2) were also load-responsive in a murine osteocyte (IDG-SW3 cells) bioreactor model. Our findings indicate that an existing mechanosensitive osteocytic repair program is suppressed by MM cells, which can be reinvigorated via a brief single loading session. It suggests that exercise-based interventions may be beneficial to restore bone mass through endochondral ossification programs in patients with MM.

Bone disease↗

PubMed2006

CD200 is a new prognostic factor in multiple myeloma.

Using Affymetrix microarrays, we identified the expression of the CD200 gene in multiple myeloma cells (MMCs) of 112 patients with newly diagnosed multiple myeloma (MM). The CD200 gene was either absent or present (Affymetrix call) in 22% and 78% of MMCs, respectively. The CD200 gene is not expressed in cells of the patients' bone marrow (BM). CD200 is a membrane glycoprotein that imparts an immunoregulatory signal through CD200R, leading to the suppression of T-cell-mediated immune responses. Patients with CD200(absent) MMCs have an increased event-free survival (EFS; 24 months) compared with patients with CD200(present) MMCs (14 months), after high-dose therapy and stem cell transplantation. In a Cox proportional-hazard model, the absence or presence of CD200 expression in MMCs is predictive for EFS for patients independently of ISS stage or beta2M serum levels. Thus, CD200 is an independent prognosis factor for patients with MM that could represent a new therapeutic target in MM.

Antigens, CD↗

PubMed2006

Immunochemical, ultrastructural and electrophysiological investigations of bone-derived stem cells in the course of neuronal differentiation.

Numerous reports have highlighted the use of mesenchymal stem cells (MSC) for tissue engineering because of the capacity of the cells to differentiate along the osteogenic, chondrogenic or adipogenic pathway. As MSC also display neuronal morphologies under appropriate culture conditions, the differentiation capacity of stem cells seems to be more complex than initially thought, but it requires careful characterization of the cells. This is especially the case because recently it has been suggested that neuronal differentiation of stem cells is only an artifact. Here, we investigate the sequence of ultrastructural changes of bone-derived stem cells during neuronal induction and compare these data with immunocytochemical and electrophysiological properties of the cells. For further comparative analyses, stem cells were incubated with non-neurologically inducing stressors. The stem cells were harvested from human osseous debris and were characterized morphologically, immunocytochemically and by using FACS. After 6 h of neuronal induction, the cells had assumed neuronal morphologies and expressed neuron-specific enolase, beta-III-tubulin, neurofilament-H and HNK-1, while only a subpopulation expressed CD15 and synaptophysin. However, electrical signaling could not be detected, neither spontaneously nor after electrical stimulation. Nevertheless, transmission electron microscopy revealed cellular features of neuritogenesis and synaptogenesis in the course of neuronal induction and suggested that the cells have features similar to those observed in immature neurons. Based upon the results, it can be concluded that neuronal induction had initiated the early steps of neuronal differentiation, while exposure of the cells to non-neurological stressors had caused necrotic alterations.

Bone and Bones↗

PubMed2006

Identification of a new HLA-A2-restricted T-cell epitope within HM1.24 as immunotherapy target for multiple myeloma.

OBJECTIVE: The aim of this study was identification of human leukocyte antigen (HLA)-A2-restricted T-cell epitopes within the HM1.24 antigen as target for multiple myeloma (MM)-directed specific peptide-based immunotherapy. METHODS: The HM1.24 sequence was scanned for immunogenic peptides using the HLA-binding prediction software SYFPEITHI and BIMAS. Peripheral blood mononuclear cells from HLA-A2(+) healthy volunteers/blood donors (ND) were stimulated with autologous HM1.24-peptide-loaded dendritic cells, and expanded in vitro. Activation of T cells was assessed by ELISpot and cytotoxicity by (51)Chromium ((51)Cr)-release assays. T2-cells pulsed with irrelevant peptide, the HM1.24(-)/HLA-A2(+) breast carcinoma cell line MCF-7 and the HM1.24(+)/HLA-A2(-) myeloma cell line RPMI-8226 were used as controls. Expression of the HM1.24 gene (BST2) was assessed using purified plasma cells and Affymetrix-U133A+B microarrays. Frequency of peptide-specific CD8(+) T cells was detected using the flow-cytometric tetramer technique. RESULTS: Of eight nona-peptides with the highest probability of binding to HLA-A2, the HM1.24 aa22-30 peptide (LLLGIGILV) showed the most frequent activation of CD8(+) T cells in healthy volunteers (specific activation in 8 of 11 [73%] ND; compared with 5-19% for the 7 other HM1.24 peptides). Antigen recognition by the HM1.24 aa22-30-specific CD8(+) T cells was HLA-A2-restricted (ELISpot with HLA-A2-blocking antibodies: median, 15; range, 14-18 spots/well; isotype-control antibodies: median, 47; range, 44-48). HM1.24-aa22-30-specific CD8(+) T cells lysed HLA-A2(+) myeloma-derived cell lines ((51)Cr-release assay: XG-1 vs MCF-7, 91% vs 0%; U266 vs MCF-7, 38% vs 4.2%; IM-9 vs RPMI-8226, 22% vs 0%). Using the cross-reactive Neisseria meningitidis peptide LLSLGIGILV-specific CD8(+) T cells recognizing target cells loaded with the HM1.24 aa22-30 peptide (LLLGIGILV) as well as the myeloma-derived cell line U266 could be expanded from MM patients. The HM1.24 gene was expressed at comparable levels by plasma cells from 65 MM patients, 7 patients with monoclonal gammopathy of undetermined significance, and 7 ND. CONCLUSIONS: HM1.24 aa22-30 is a newly identified HLA-A2-restricted T-cell epitope that is processed and presented by major histocompatibility complex class I. Specifically activated CD8(+) T cells are able to lyse MM cell lines. We conclude that HM1.24 aa22-30 represents a suitable candidate target for a specific peptide-based immunotherapy of MM.

Antigens, CD↗

PubMed2006

Microarray-based understanding of normal and malignant plasma cells.

Plasma cells (PCs) develop from B lymphocytes following stimulation by antigen and express a genetic program aimed at the synthesis of immunoglobulins. This program includes the induction of genes coding for transcription factors such as PRDM1, X-box-binding protein 1 and BHLHB3, cell-surface molecules such as CD138/syndecan-1, and for the unfolded protein response. We review how the microarray technology has recently contributed to the understanding of the biology of this rare but essential cell population and its transformation into premalignant and malignant PCs.

B-Lymphocytes↗

PubMed2005

Expression of EGF-family receptors and amphiregulin in multiple myeloma. Amphiregulin is a growth factor for myeloma cells.

A hallmark of plasma cells is the expression of syndecan-1, which has major functions in epithelial cells, in particular as the coreceptor of heparin-binding growth factors. We previously found that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a growth factor for malignant plasma cells. As amphiregulin (AREG) is another heparin-binding factor of the EGF family, we investigated its role in multiple myeloma (MM). Using Affymetrix DNA microarrays, we show here that the AREG gene was expressed by purified primary myeloma cells from 65 patients and that the expression was higher than in normal bone marrow (BM) plasma cells or plasmablastic cells. AREG stimulated IL-6 production and growth of BM stromal cells. Using real-time reverse transcriptase-polymerase chain reaction, we found that MM cells expressed ErbB receptors and that AREG promoted their growth. Furthermore, PD169540 (a pan-ErbB inhibitor) and IRESSA (an ErbB1-specific inhibitor) induced apoptosis of primary myeloma cells from 10/14 and 4/14 patients, respectively, and there was a synergistic effect with dexamethasone. Altogether, our data provide strong evidence that AREG plays an important role in the biology of MM and emphasize the advantages of using ErbB inhibitors, which might target myeloma cells as well as the tumor environment.

Amphiregulin↗

PubMed2005

The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature.

B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have been shown to promote multiple myeloma (MM) cell growth. We show that the main site of production for BAFF and APRIL is the bone marrow (BM) environment, and that production is mainly by monocytes and neutrophils. In addition, osteoclasts produce very high levels of APRIL, unlike BM stromal cells. Myeloma cells (MMCs) express TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor), the receptor of BAFF/APRIL, at varying levels. TACI expression is a good indicator of a BAFF-binding receptor. Expression data of purified MMCs from 65 newly diagnosed patients have been generated using Affymetrix microarrays and were analyzed by supervised clustering of groups with higher (TACI(hi)) versus lower (TACI(lo)) TACI expression levels. Patients in the TACI(lo) group had clinical parameters associated with bad prognosis. A set of 659 genes was differentially expressed between TACI(hi) and TACI(lo) MMCs. This set makes it possible to efficiently classify TACI(hi) and TACI(lo) MMCs in an independent cohort of 40 patients. TACI(hi) MMCs displayed a mature plasma cell gene signature, indicating dependence on the BM environment. In contrast, the TACI(lo) group had a gene signature of plasmablasts, suggesting an attenuated dependence on the BM environment. Taken together, our findings suggest using gene expression profiling to identify the group of patients who might benefit most from treatment with BAFF/APRIL inhibitors.

B-Cell Activating Factor↗

PubMed2005

Delineation of distinct subgroups of multiple myeloma and a model for clonal evolution based on interphase cytogenetics.

To delineate multiple myeloma (MM) subgroups and their clonal evolution, we analyzed 81 newly diagnosed patients by interphase fluorescence in situ hybridization using a comprehensive probe set for 10 chromosomes and two IGH rearrangements. A median of 5 probes per patient displayed aberrant signal numbers (range, 1-10). Additional copies most frequently found were for 15q22, 19q13, 9q34, 11q23, and 1q21. Losses commonly observed were of 13q14.3, 17p13, and 22q11. Predominance of gain or loss was quantified by a copy number score (CS) for each patient. Two peaks (CS = +3 and CS = 0) were found by plotting patient copy number scores over CS values corresponding to hyperdiploid and nonhyperdiploid MM. Cluster analysis revealed four major branches: (i) gain of 9q, 15q, 19q, and/or 11q; (ii) deletion of 13q and t(4;14); (iii) t(11;14); and (iv) gain of 1q. Statistical modeling of an oncogenetic tree indicated that early independent events were gain of 15q/9q and/or 11q, t(11;14); deletion of 13q followed by t(4;14); and gain of 1q. Aberrations of 17p13, 22q11, 8p12, and 6q21 were found as subsequent events. MM with gain of 1q was delineated as a subentity with significantly higher beta-2-microglobulin and lower hemoglobin levels, indicating a poor prognosis. From our results, we propose a model of MM for clonal evolution.

Evolution, Molecular↗

PubMed2005

High incidence and intraclonal heterogeneity of chromosome 11 aberrations in patients with newly diagnosed multiple myeloma detected by multiprobe interphase FISH.

In multiple myeloma, additional copies of chromosome 11 material, reported to confer an unfavorable prognosis, have been found in 20-45% of patients. To assess the incidence and extent of chromosome 11 aberrations, we performed interphase fluorescence in situ hybridization on CD138+ bone marrow plasma cells of 50 newly diagnosed myeloma patients, using seven locus-specific probes for chromosome 11, one for 13q14.3, and a probe set for translocation t(11;14). In 33 of 50 patients, chromosome 11 aberrations were found. Results indicated a marked intraclonal heterogeneity: in 13 patients, trisomy 11; in 10 patients, subclones with trisomy 11 and partial trisomies 11q coexisted; in 6 patients, only a partial trisomy 11q; and in 6 patients, a tetrasomy or partial tetrasomy 11. The coexistence of subclones with varying extent and copy numbers of chromosome 11 material indicates ongoing structural changes and clonal evolution. Hybridization results delineated 11q23 and 11q25 as the most frequently gained regions, which supports a relevant pathogenetic role of genes on 11q23 and 11q25. To confirm the high incidence of 11q23 gains, a further 50 patients (total n=100) were analyzed for 11q23 and 13q14.3. Myeloma with gains of 11q23 showed a low frequency of deletion 13q14.3 and may prove to be a distinct subgroup of this disease.

Adult↗

PubMed2004

Human reaming debris: a source of multipotent stem cells.

The biological characteristics of human reaming debris (HRD) generated in the course of surgical treatment of long bone diaphyseal fractures and nonunions are still a matter of dispute. Therefore, the objective of the present investigation has been to characterize the intrinsic properties of human reaming debris in vitro. Samples of reaming debris harvested from 12 patients with closed diaphyseal fractures were examined ultrastucturally and were cultured under standard conditions. After a lag phase of 4-7 days, cells started to grow out from small bone fragments and established a confluent monolayer within 20-22 days. The cells were characterized according to morphology, proliferation capacity, cell surface antigen profile, and differentiation repertoire. The results reveal that human reaming debris is a source of multipotent stem cells which are able to grow and proliferate in vitro. The cells differentiate along the osteogenic pathway after induction and can be directed toward a neuronal phenotype, as has been shown morphologically and by the expression of neuronal markers after DMSO induction. These findings have prompted interest in the use of reaming debris-derived stem cells in cell and bone replacement therapies.

Adult↗