Bone marrow stroma-derived PGE2 protects BCP-ALL cells from DNA damage-induced p53 accumulation and cell death

Background B cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer. BCP-ALL blasts typically retain wild type p53, and are therefore assumed to rely on indirect measures to suppress transformation-induced p53 activity. We have recently demonstrated that the second messenger cyclic adenosine monophosphate (cAMP) through activation of protein kinase A (PKA) has the ability to inhibit DNA damage-induced p53 accumulation and thereby promote survival of the leukaemic blasts. Development of BCP-ALL in the bone marrow (BM) is supported by resident BM-derived mesenchymal stromal cells (MSCs). MSCs are known to produce prostaglandin E2 (PGE2) which upon binding to its receptors is able to elicit a cAMP response in target cells. We hypothesized that PGE2 produced by stromal cells in the BM microenvironment could stimulate cAMP production and PKA activation in BCP-ALL cells, thereby suppressing p53 accumulation and promoting survival of the malignant cells. Methods Primary BCP-ALL cells isolated from BM aspirates at diagnosis were cocultivated with BM-derived MSCs, and effects on DNA damage-induced p53 accumulation and cell death were monitored by SDS-PAGE/immunoblotting and flow cytometry-based methods, respectively. Effects of intervention of signalling along the PGE2-cAMP-PKA axis were assessed by inhibition of PGE2 production or PKA activity. Statistical significance was tested by Wilcoxon signed-rank test or paired samples t test. Results We demonstrate that BM-derived MSCs produce PGE2 and protect primary BCP-ALL cells from p53 accumulation and apoptotic cell death. The MSC-mediated protection of DNA damage-mediated cell death is reversible upon inhibition of PGE2 synthesis or PKA activity. Furthermore our results indicate differences in the sensitivity to variations in p53 levels between common cytogenetic subgroups of BCP-ALL. Conclusions Our findings support our hypothesis that BM-derived PGE2, through activation of cAMP-PKA signalling in BCP-ALL blasts, can inhibit the tumour suppressive activity of wild type p53, thereby promoting leukaemogenesis and protecting against therapy-induced leukaemic cell death. These novel findings identify the PGE2-cAMP-PKA signalling pathway as a possible target for pharmacological intervention with potential relevance for treatment of BCP-ALL

A study of the centrally produced phiphi system in pp interactions at 450 GeV/c

The reaction pp to pfps(K+K-K+K-) in which the K+K-K+K- system is centrally produced has been studied at 450 GeV/c. Phi phi production has been found to dominate this reaction and is compatible with being produced by double Pomeron exchange. An angular analysis of the phi phi system favours JPC = 2++ and its dPT dependence is similar to that observed for glueball candidates.Comment: 11 pages, Latex, 4 Figure

A study of pseudoscalar states produced centrally in pp interactions at 450 GeV/c

A study has been made of pseudoscalar mesons produced centrally in pp interactions. The results show that the eta and etaprime appear to have a similar production mechanism which differs from that of the pi0. The production properties of the eta and etaprime are not consistent with what is expected from double Pomeron exchange. In addition the production mechanism for the eta and etaprime is such that the production cross section are greatest when the azimuthal angle between the pT vectors of the two protons is 90 degrees.Comment: 11 pages, Latex, 3 Figure

Genome wide single cell analysis of chemotherapy resistant metastatic cells in a case of gastroesophageal adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Metastatic progression due to development or enrichment of therapy-resistant tumor cells is eventually lethal. Molecular characterization of such chemotherapy resistant tumor cell clones may identify markers responsible for malignant progression and potential targets for new treatment. Here, in a case of stage IV adenocarcinoma of the gastroesophageal junction, we report the successful genome wide analysis using array comparative genomic hybridization (CGH) of DNA from only fourteen tumor cells using a bead-based single cell selection method from a bone metastasis progressing during chemotherapy.</p> <p>Case presentation</p> <p>In a case of metastatic adenocarcinoma of the gastroesophageal junction, the progression of bone metastasis was observed during a chemotherapy regimen of epirubicin, oxaliplatin and capecitabine, whereas lung-, liver and lymph node metastases as well as the primary tumor were regressing. A bone marrow aspirate sampled at the site of progressing metastasis in the right iliac bone was performed, and single cell molecular analysis using array-CGH of Epithelial Specific Antigen (ESA)-positive metastatic cells, and revealed two distinct regions of amplification, 12p12.1 and 17q12-q21.2 amplicons, containing the KRAS (12p) and ERBB2 (HER2/NEU) (17q) oncogenes. Further intrapatient tumor heterogeneity of these highlighted gene copy number changes was analyzed by fluorescence in situ hybridization (FISH) in all available primary and metastatic tumor biopsies, and ErbB2 protein expression was investigated by immunohistochemistry.</p> <p>ERBB2 was heterogeneously amplified by FISH analysis in the primary tumor, as well as liver and bone metastasis, but homogenously amplified in biopsy specimens from a progressing bone metastasis after three initial cycles of chemotherapy, indicating a possible enrichment of erbB2 positive tumor cells in the progressing bone marrow metastasis during chemotherapy. A similar amplification profile was detected for wild-type KRAS, although more heterogeneously expressed in the bone metastasis progressing on chemotherapy. Correspondingly, the erbB2 protein was found heterogeneously expressed by immunohistochemical staining of the primary tumor of the gastroesophageal junction, while negative in liver and bone metastases, but after three initial cycles of palliative chemotherapy with epirubicin, oxaliplatin and capecetabine, the representative bone metastasis stained strongly positive for erbB2.</p> <p>Conclusion</p> <p>Global analysis of genetic aberrations, as illustrated by performing array-CGH analysis on genomic DNA from only a few selected tumor cells of interest sampled from a progressing bone metastasis, can identify relevant therapeutic targets and genetic aberrations involved in malignant progression, thus emphasizing the importance and feasibility of this powerful tool on the road to more personalized cancer therapies in the future.</p

A kinematical selection of glueball candidates in central production

A study of central meson production as a function of the difference in transverse momentum ($dP_T$) of the exchanged particles shows that undisputed $q \overline q$ mesons are suppressed at small $dP_T$ whereas the glueball candidates are enhanced

A partial wave analysis of the centrally produced K+K−K^{+}K^{-} and Ks0Ks0K^{0}_{s}K^{0}_{s} systems in pp interactions at 450 GeV/c and new information on the spin of the f1f_{1} (1710)

A partial wave analysis of the centrally produced K+K- and K0K0 channels has been performed in pp collisions using an incident beam momentum of 450 GeV/c. An unambiguous physical solution has been found in each channel. The striking feature is the observation of peaks in the S-wave corresponding to the f0(1500) and fJ(1710) with J = 0. The D-wave shows evidence for the f2(1270)/a2(1320), the f2(1525) and the f2(2150) but there is no evidence for a statistically significant contribution in the D-wave in the 1.7 GeV mass region

A kinematical selection of glueball candidates in central production

A study of central meson production as a function of the difference in transverse momentum ($dP_T$) of the exchanged particles shows that undisputed $q \overline q$ mesons are suppressed at small $dP_T$ whereas the glueball candidates are enhanced

A study of the centrally produced 4pi channel in pp interactions at 450 GeV/c

The reaction pp -> pf (pi+pi-pi+pi-) ps has been studied at 450 GeV/c in an experiment designed to search for gluonic states. A spin analysis has been performed and the dPT filter applied. In addition to the well known f1(1285) there is evidence for two JPC=2-+ states called the eta2(1620) and eta2(1875) and a broad scalar called the f0(2000). The production of these states as a function of the dPT kinematical filter shows the behaviour expected for qqbar states. In contrast, there is evidence for two states at 1.45 GeV and at 1.9 GeV which do not show the behaviour observed for qqbar states.Comment: 14 pages, Latex, 3 Figure

Identification of target genes for wild type and truncated HMGA2 in mesenchymal stem-like cells

Background The HMGA2 gene, coding for an architectural transcription factor involved in mesenchymal embryogenesis, is frequently deranged by translocation and/or amplification in mesenchymal tumours, generally leading to over-expression of shortened transcripts and a truncated protein. Methods To identify pathways that are affected by sarcoma-associated variants of HMGA2, we have over-expressed wild type and truncated HMGA2 protein in an immortalized mesenchymal stem-like cell (MSC) line, and investigated the localisation of these proteins and their effects on differentiation and gene expression patterns. Results Over-expression of both transgenes blocked adipogenic differentiation of these cells, and microarray analysis revealed clear changes in gene expression patterns, more pronounced for the truncated protein. Most of the genes that showed altered expression in the HMGA2-overexpressing cells fell into the group of NF-κB-target genes, suggesting a central role for HMGA2 in this pathway. Of particular interest was the pronounced up-regulation of SSX1, already implicated in mesenchymal oncogenesis and stem cell functions, only in cells expressing the truncated protein. Furthermore, over-expression of both HMGA2 forms was associated with a strong repression of the epithelial marker CD24, consistent with the reported low level of CD24 in cancer stem cells. Conclusions We conclude that the c-terminal part of HMGA2 has important functions at least in mesenchymal cells, and the changes in gene expression resulting from overexpressing a protein lacking this domain may add to the malignant potential of sarcomas