Biomedical subjects

R Bataille

Publications and source records attributed to R Bataille.

At least 73 records · Page 4Linked to original sources

PubMed1998

Detection of t(11;14) using interphase molecular cytogenetics in mantle cell lymphoma and atypical chronic lymphocytic leukemia.

The chromosomal translocation t(11;14)(q13;q32) fuses the IGH and CCND1 genes and leads to cyclin D1 overexpression. This genetic abnormality is the hallmark of mantle cell lymphoma (MCL), but is also found in some cases of atypical chronic lymphocytic leukemia (CLL), characterized by a poor outcome. For an unequivocal assessment of this specific chromosomal rearrangement on interphase cells, we developed a set of probes for fluorescence in situ hybridization (FISH). Northern blotting was performed for analysis of the cyclin D1 expression in 18 patients. Thirty-eight patients, with either a typical MCL leukemic phase (17 patients) or atypical CLL with an MCL-type immunophenotype, i.e., CD19-, CD5+, CD23-/low, CD79b/sIgM(D)++, and FMC7+ (21 patients), were analyzed by dual-color interphase FISH. We selected an IGH-specific BAC probe (covering the JH and first constant regions) and a commercially available CCND1 probe. An IGH-CCND1 fusion was detected in 28 of the 38 patients (17 typical MCL and 11 cases with CLL). Cyclin D1 was not overexpressed in two patients with typical MCL and an IGH-CCND1 fusion. In view of the poor prognosis associated with MCL and t(11;14)-positive CLL, we conclude that this set of probes is a valuable and reliable tool for a rapid diagnosis of these entities.

Adult↗

PubMed1998

The absence of CD56 (NCAM) on malignant plasma cells is a hallmark of plasma cell leukemia and of a special subset of multiple myeloma.

In this study, we show that malignant plasma cells from patients with either primary (n=12) or secondary (n=15) plasma cell leukemia (PCL) do not express CD56 at all, neither in the bone marrow nor the peripheral blood in 81% of cases. On the other hand, multiple myeloma (MM) at diagnosis overexpress it in 63 of 94 (67%) cases (P=0.0001). In three secondary PCL evaluated serially, CD56 was also lacking at diagnosis showing that CD56 is not downregulated at the end stage of the disease but rather not upregulated in this subset of patients. This last concept is strengthened by the observation that 29% of MM patients lacking CD56 or weakly expressing it at diagnosis present a detectable leukemic phase vs 11% only in CD561 MM (P=0.06). Forty percent of all the CD56(-/weak) malignant plasma cell disorders present or develop a leukemic phase vs only 15% of CD56+ cases (P < 0.008). CD56(-/weak) MM subset is also associated with a significantly less aggressive osteolytic potential (P=0.012). We conclude that the lack or weak expression of CD56 is a characteristic feature of PCL but also delineates a special subset of MM at diagnosis mainly characterized by a lower osteolytic potential and a trend for malignant plasma cells to circulate in the peripheral blood more overtly.

Bone Marrow↗

PubMed1998

Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients.

We retrospectively investigated the feasibility and the toxicity of autologous stem cell transplantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high-dose melphalan (HDM) alone (n = 18) or in combination with 12 Gy total body irradiation (n = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow-up of 14 months, the OS and the EFS rates at 4 years were 57.1% (+/-10.8) and 29.9% (+/-14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance < 30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4-year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra-haematological toxicity, ASCT should not be considered in other cases.

Adult↗

PubMed1998

Interleukin-1 in multiple myeloma: producer cells and their role in the control of IL-6 production.

We studied the role of interleukin (IL)-1beta in patients with multiple myeloma. By in situ hybridization and immunochemistry, myeloid and megakaryocytic cells expressed high levels of the IL-1beta gene and produced IL-1beta. Myeloma cells less potently expressed the IL-1beta gene and IL-1beta protein. IL-1beta gene expression was not constitutive since it was detected in the bone marrow myeloma cells of two patients, unlike circulating tumoural cells. In addition, nine myeloma cell lines failed to express the IL-1beta gene and this expression could not be induced by 12 different cytokines. We demonstrated that IL-1 was mainly responsible for IL-6 production in the tumoural environment through a PGE2 loop. In fact, an IL-1 receptor antagonist (IL-1RA) blocked PGE2 synthesis and IL-6 production by 80%; this blockage could be reversed by adding synthetic PGE2. Similar findings were found with indomethacin, an inhibitor of cyclooxygenase that blocks PGE2 synthesis. Taken together, these data emphasize the possibility of blocking IL-1 by using IL-1RA or other antagonists in order to block IL-6 production, which is a major tumoural survival and proliferation factor.

Adult↗

PubMed1998

CD28, a marker associated with tumoral expansion in multiple myeloma.

CD28 expression was thoroughly investigated on plasma cells of monoclonal gammopathy of undetermined significance, multiple myeloma (MM), and human myeloma cell lines. CD28+ plasma cells were detected in 19% of 31 monoclonal gammopathy of undetermined significance, 41% of 116 MM, and 100% of 13 human myeloma cell lines. CD28+ myeloma cells were detected in 21 of 79 (26%) MM cases at diagnosis, 13 of 22 (59%) at medullary relapse (P < 0.009), and 14 of 15 (93%) at extramedullary relapse (P = 0.05), including 10 of 10 (100%) secondary plasma cell leukemias (P = 0.05). Serial studies in individual patients confirmed the emergence of CD28+ myeloma cells with tumoral expansion and treatment failure. This was significantly correlated with the expression of CD28 ligand, i.e., CD86 (but not CD80), and with an increase in the proliferative activity (labeling index) of myeloma cells in bone marrow. Whereas the expression of CD56 defines a particular subset of myeloma patients, CD28 is the only antigen for which expression correlates with tumor progression. Our data show that an aggressive compartment of CD28+ and CD86+ myeloma cells emerges during the course of MM in vivo, indicating that CD28 could be aberrantly expressed on highly malignant (possibly mutated) myeloma cells. Conversely, a subset of proliferative plasmablasts coexpressing CD28 and CD86 could be the normal counterpart of the clonogenic myeloma stem cell because a subset of CD28+ plasma cells was observed in 6 of 6 cases of reactive plasmocytosis.

Antigens, CD↗

PubMed1997

Metalloproteinases in multiple myeloma: production of matrix metalloproteinase-9 (MMP-9), activation of proMMP-2, and induction of MMP-1 by myeloma cells.

Multiple myeloma is a very devastating cancer with a high capacity to destroy bone matrix. Matrix metalloproteinases (MMPs) play a critical role in bone remodeling and tumor invasion. In this study, we have investigated the involvement of interstitial collagenase (MMP-1) and gelatinases (MMP-2 and MMP-9) in the biology of multiple myeloma. We show (1) that myeloma cells express MMP-9 and (2) that this expression is not subjected to regulation either by interleukin-6 (IL-6), the major myeloma cell growth factor, or by other cytokines involved in the multiple myeloma cytokine network. In the tumoral environment, we show that bone marrow stromal cells express MMP-1 and MMP-2. Whereas MMP-1 is positively regulated by IL-1beta, tumor necrosis factor-alpha, and Oncostatin M, MMP-2 is not modulated by any of these cytokines. To evaluate whether myeloma cells can modify the bone marrow stromal environment, we have examined these MMP activities in coculture. Interestingly, we have observed an upregulation of MMP-1 and a partial conversion of the proMMP-2 into its activated form. We conclude that the increase of MMP activity produced or induced by myeloma cells in these cocultures could favor bone resorption and tumor invasion. Inhibition of such activities could represent a new therapeutical approach in multiple myeloma.

Antineoplastic Agents↗

PubMed1997

Multiple myeloma.

Explore the source record for details and available documents.

Antineoplastic Agents↗

PubMed1997

Molecular cytogenetic abnormalities in multiple myeloma and plasma cell leukemia measured using comparative genomic hybridization.

Comparative genomic hybridization (CGH) was used to identify recurrent regions of DNA sequence loss and gain in 21 multiple myeloma (MM) and plasma cell leukemia (PCL) primary tumor specimens and cell lines. Multiple regions of non-random sequence loss and gain were observed in 8/8 primary advanced stage tumors and 13/13 cell lines. Identification of sequence copy number changes was facilitated by statistical analyses that reduce subjectivity associated with identification of copy number changes and by requiring that sequence changes are visible using both red- and green-labeled tumor DNA. Loss of sequence on 13q and 14q and gain of sequence on 1q and chromosome 7 occurred in 50-60% of the population. In general, cell lines carry more and larger regions of sequence gain and loss than primary tumors. Regions of sequence copy number change that recur among MM cell lines and primary tumors include, in order of prevalence, enh(1q12qter), dim(13), enh(7), enh(3q22q29), enh(11q13.3qter), dim(14q11.2q31), enh(8q21qter), enh(3p25pter), dim(17p11.2p13), and dim(6q22.1q23). Population distributions of genome-wide changes in primary tumors reveal "hot-spots" of sequence loss from 13q12.1-q21, 13q32-q34, 14q11.2-q13, and 14q23-q31. Genomic changes detected using CGH are consistent with those identified using banding analyses, although recurrent involvement of additional regions of the genome are also evident. A higher prevalence of genomic changes is visible using CGH compared to banding. Identification of recurrent regions of sequence gain and loss provides opportunities to identify regions of the genome that may be involved in the malignant phenotype and/or disease progression.

DNA, Neoplasm↗

PubMed1997

Analysis of platelet recovery after autologous transplantation with G-CSF mobilized CD34+ cells purified from leukapheresis products.

We studied platelet recovery in relation to graft content in CFUs and CD34+ cells in 31 patients with multiple myeloma (21) or non-Hodgkin lymphoma (10) receiving marrow-ablative therapy followed by autologous transplantation with G-CSF mobilized CD34+ cells purified from leukapheresis products. Twelve patients had prolonged post-transplantation thrombopenia (> or = 14 days): their graft contents in CD34+ cells, CFU-GM and BFU-E were significantly inferior to those of patients with rapid platelet recovery. Although numbers of infused CD34+ cells and CFU-GM or BFU-E were well correlated, the graft content in CD34+ cells was the only parameter predictive of platelet recovery (r = -0.38, p = 0.04), with a threshold of 2.5 x 10(6) CD34+ cells/kg. However, because rapid platelet reconstitution was obtained for 4 of 16 patients re-infused with < 2.5 x 10(6) CD34+ cells/kg, we investigated whether the graft CFU-MK content might be a better predictor of platelet reconstitution than the CD34+ cell content. Eighteen CD34 grafts were studied for CFU-MK content: CD34 and CFU-MK contents were weakly correlated (r = 0.52, p = 0.03), but there was no correlation between numbers of infused CFU-MK and time to platelet recovery. We conclude that, for autologous CD34 grafts, CFU-MK assays, like CFU-GM or BFU-E assays, cannot be used to predict platelet recovery. A CD34+ cell content > or = 2.5 x 10(6)/kg remains the only reliable indicator of the platelet reconstitution capacity of a CD34 graft.

Adult↗

PubMed1997

Pathogenesis and management of bone lesions in multiple myeloma.

Osteolytic lesions are among the hallmarks of multiple myeloma (MM). On the other hand, they are rare in B cell malignancies other than MM. Data have shown a close relationship between myeloma cell growth factors and factors involved in the occurrence of bone lesions in MM. Biophosphonates, which are potent inhibitors of bone resorption to control MM-induced hypercalcemia, are of interest due to their ability to slow the progression of MM bone disease.

Bone Neoplasms↗

PubMed1997

CD40 and CD95 induce programmed cell death in the human myeloma cell line XG2.

We have previously demonstrated that CD40 stimulation induced a cellular growth arrest of the highly CD40-positive myeloma cell line XG2. To further characterize this inhibition of proliferation, we looked for a possible induction of apoptosis. Since no DNA fragmentation could be detected, we used newly described techniques that enable detection of apoptosis independently of DNA degradation, i.e. supravital exposure to propidium iodide (PI) and Annexin V labelling. We demonstrated that CD40 effectively induced programmed cell death. Furthermore, we have shown that CD95 (Fas) stimulation significantly enhanced the CD40-induced apoptosis.

Annexin A5↗

PubMed1997

Comparative genomic hybridization is a powerful tool, complementary to cytogenetics, to identify chromosomal abnormalities in childhood acute lymphoblastic leukaemia.

Cytogenetics has a strong prognostic value in childhood acute lymphoblastic leukaemia (ALL), but results are often incomplete because of the poor chromosome morphology. To improve this analysis, we tested comparative genomic hybridization (CGH) for the detection of chromosomal imbalances. 72 children were retrospectively analysed using CGH. Only 53% of the patients had been fully banded by standard methods. With CGH, 36 patients retained a normal chromosomal profile and 36 had unbalanced abnormalities. No amplification was detected. Fluorescence in situ hybridization (FISH) with centromeric and unique sequence probes was used in those cases with discrepancies or unsuccessful karyotype to validate CGH results. CGH enabled clear identification of unbalanced chromosomal abnormalities, even in some cases which had a normal karyotype. In view of the strong prognostic value of hyperdiploidy in childhood ALL, CGH appears to be a powerful technique, complementary to conventional cytogenetics.

Adolescent↗

PubMed1997

Comparative genomic hybridization detects genomic abnormalities in 80% of follicular lymphomas.

Comparative genomic hybridization (CGH) was used to analyse 34 follicular lymphoma (FL) samples. 27 samples showed DNA sequence copy number changes of at least one genomic region (26 samples with at least one gain and nine with at least one loss). Some chromosomes or chromosomal regions were preferentially involved. The most frequently gained regions were chromosome 18q (29% of samples), chromosome X (21%), chromosome 7 (18%), chromosomes 2, 6p and 8q (12%). Two regions were preferentially lost: 6q (12%) and 17p (9%). All these gained and lost regions have been previously reported in cytogenetic studies, confirming the accuracy of CGH in detecting genetic abnormalities in FL. 21% of samples displayed normal profiles, probably reflecting the absence of unbalanced abnormality, which is also in agreement with the cytogenetic data. In conclusion, we showed that CGH is an accurate, reliable and rapid method and we propose the inclusion of CGH in the evaluation of FL at diagnosis.

Chromosome Aberrations↗

PubMed1997

The retinoblastoma susceptibility gene RB-1 in multiple myeloma.

Genetic mechanisms leading to the development of multiple myeloma (MM) remain poorly understood. Given the frequency of chromosome 13 deletion in MM and the localization in 13q14 of the retinoblastoma susceptibility gene RB-1, an involvement of RB-1 in MM pathogenesis has been proposed. Moreover, interleukin-6 (IL-6) has been shown to be the main growth factor for MM in vitro and in vivo. The product of the RB-1 gene (pRB) can down-regulate IL-6 gene expression. Absence of pRB may then induce an autocrine IL-6 expression in myeloma cells and contribute to the autonomous growth of MM. As assessed in this review, heterozygous deletion of RB-1 is very common in MM but does not alter gene transcription and protein expression. Nevertheless, homozygous deletion of RB-1 has been identified in some MM patients with advanced disease and in the IL-6-autocrine human myeloma cell line U266. Thus, even if inactivation of RB-1 appears to be only a rare and late oncogenic event in MM and is not likely to represent the main mechanism involved in IL-6 up-regulation in MM, definitive assessment of the actual role played by RB-1 in MM pathogenesis still needs further investigation particularly the examination of pRB function.

Cell Division↗

PubMed1997

New insights in the clinical biology of multiple myeloma.

In the last 5 years, numerous studies have been devoted to the biology of multiple myeloma (MM) and of the monoclonal plasma cell process termed monoclonal gammopathy of undetermined significance (MGUS). Presenting features of MM are changing, with a shift from symptomatic to indolent or localized presentations. Post-MGUS MM are frequent. There is now striking evidence that myeloma cells have an abnormal biology, especially an aberrant differentiation and survival pathway inside the bone marrow. Their aberrant phenotype and genotype are probably responsible for this. Several studies have emphasized the essential role of interleukin-6 (IL-6) as a survival and growth factor for myeloma cells and the interest in anti-IL-6 therapy in MM.

Bone Neoplasms↗

PubMed1997

Immunoglobulins D and M multiple myeloma variants are heavily mutated.

Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of malignant plasma cells within the bone marrow. Previous studies that have examined the Ig VH genes of IgG and IgA MMs have shown the presence of somatic mutations, suggesting that in these cases, the myeloma precursor cell passed through the phase of antigenic selection within the germinal center but is no longer exposed to the somatic mutation process. However, no information about this matter is available in the rare IgD and IgM MM variants. Therefore, we have analyzed the Ig VH genes of three IgD, one IgM, and one biclonal (IgG and IgM) MM for the presence of somatic mutations. Our study demonstrates that all of these myeloma clones have accumulated a high number of somatic mutations within their Ig VH genes but show no intraclonal variation. Moreover, proof that the clone sustained a strong antigenic selection pressure could be provided in three cases (one IgD and two IgMs). Therefore, this study strongly implies that IgD and IgM MMs emerge from a postgerminal center preswitched B cell that is no longer exposed to the somatic mutation process or able to undergo further isotype switching in vivo.

Amino Acid Sequence↗

PubMed1996

Myeloma cell growth arrest, apoptosis, and interleukin-6 receptor modulation induced by EB1089, a vitamin D3 derivative, alone or in association with dexamethasone.

We have previously shown that malignant plasma cells expressed the specific receptor for 1,25-dihydroxyvitamin D3 and that this derivative could significantly inhibit the proliferation of such malignant cells. More recently, new vitamin D3 derivatives have been generated with extraordinarily potent inhibitory effects on leukemic cell growth in vitro. These new data prompted us to (re)investigate the capacity of such new vitamin D3 derivatives to inhibit myeloma cell growth in comparison with that of dexamethasone, a potent antitumoral agent in multiple myeloma. In the current study, we show that EB1089, a new vitamin D3 derivative, (1) induces G1 growth arrest of human myeloma cells, which is only partially reversed by interleukin-6 (IL-6); (2) induces apoptosis in synergy with dexamethasone, IL-6, leukemia-inhibitory factor, and Oncostatin M, with an agonistic anti-gp130 monoclonal antibody being unable to prevent this apoptosis; (3) downregulates both the gp80 (ie, the alpha chain of the IL-6 receptor [IL-6Ralpha]) expression on malignant plasma cells and the production of soluble IL-6Ralpha, and finally (4) inhibits the deleterious upregulation of gp80 expression induced by dexamethasone while limiting the dexamethasone-induced upregulation of gp130 expression. Considering that these in vitro effects of EB1089 have been observed at doses obtainable in vivo (without hypercalcemic effects), our present data strongly suggest that EB1089 could have a true interest in the treatment of multiple myeloma, especially in association with dexamethasone.

Antigens, CD↗

PubMed1996

Interleukin-10 is a growth factor for human myeloma cells by induction of an oncostatin M autocrine loop.

We have a previously reported that interleukin-10 (IL-10) is a potent but IL-6-unrelated growth factor for freshly explanted myeloma cells (Lu et al, Blood 85:2521, 1995). We have also shown that exogenous IL-10 supported the growth of XG-1 and XG-2 human myeloma cell lines (HMCL) through an IL-6-independent mechanism. (Lu et al, Blood 85:2521, 1995). Because the IL-10 receptor does not involve the gp 130 IL-6 transducer, we have attempted to elucidate the mechanisms of IL-10 action on myeloma cells. Our results indicate that the myeloma cell growth factor activity of IL-10 was abrogated by an antibody to the gp 130 IL-6 transducer, indicating that it was mediated through one of the gp 130-activating cytokines. We found that myeloma cells from XG-1 and XG-2 HMCL and from 5 of 6 patients' tumoral samples produced oncostatin M (OM) constitutively but failed to produce IL-6, IL-11 and leukemia-inhibitory factor (LIF). The autocrine OM was inactive in the absence of IL-10 due to lack of a functional OM receptor on myeloma cells. IL-10, by inducing the receptor for LIF (LIFR), produced a functional autocrine OM loop in XG-1 and XG-2 cells and in primary myeloma cells from 2 patients. We also found that some myeloma cell lines (XG-4, XG-6, and XG-7) an fresh myeloma cells from 3 of 6 patients produced an autocrine IL-10 and that these cells constitutively expressed LIFR. One HMCL (XG-7) produced IL-10, OM, and IL-6 an expressed LIFR. The XG-7 cells used OM and IL-6 as autocrine growth factors. We have previously shown that IL-10 could induce IL-11 receptor in myeloma cells and confer on them sensitivity to IL-11 (Lu et al, FEBS Lett 377:515, 1995). Taken together, these results show that IL-10 is a key cytokine for inducing the expression of LIFR and IL-11R and possibly another uncharacterized OM coreceptor on myeloma cells and that OM and IL-10 might be produced by myeloma cells. They also emphasize that all myeloma cell growth factors reported to data involve an activation of the gp130 IL-6 transducer.

Antigens, CD↗