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ABSTRACT: Krüppel-like factor 4 is a transcription factor with anti-proliferative effects in differentiated cells, but with the ability to reprogram adult cells into cell-cycling pluripotent cells. In cancer, Krüppel-like factor 4 acts either as anti-oncogene or oncogene. Krüppel-like factor 4 gene expression was analyzed using Affymetrix microarrays in Multiple Myeloma. We generated conditionally expressing Krüppel-like factor 4 myeloma cell lines to investigate its function in Myeloma Biology. Krüppel-like factor 4 gene expression is high in normal plasma cells, but reduced in primary Multiple Myeloma cells of 2 thirds of patients. It is not expressed by any human myeloma cell line due to promoter methylation. Conditional expression of Krüppel-like factor 4 led to a complete cell cycle blockade, mainly in G1 phase, with no major apoptosis. This blockade is associated with induction of p21Cip1 and p27Kip1 in cell lines with an intact p53 pathway, and of p27Kip1 only in those with an impaired p53 pathway. Krüppel-like factor 4 is highly expressed in the poor prognostic MS group with t(4;14) translocation and in the good prognostic CD-1 group with t(11;14) or t(6;14). The apparent contradiction of cell cycle inhibitor Krüppel-like factor 4's expression in patients with poor prognostic could be reconciled since its expression increased myeloma cell lines resistance to melphalan. We describe for the first time that Krüppel-like factor 4 could play a critical role for controlling cell cycle and resistance to alkylating agents in Multiple Myeloma cells.
Haematologica 04/2013; · 6.42 Impact Factor
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ABSTRACT: High throughput DNA microarray has made it possible to outline genes whose expression in malignant plasma cells is associated with short overall survival of patients with Multiple Myeloma (MM). A further step is to elucidate the mechanisms encoded by these genes yielding to drug resistance and/or patients' short survival. We focus here on the biological role of the DEP (for Disheveled, EGL-10, Pleckstrin) domain contained protein 1A (DEPDC1A), a poorly known protein encoded by DEPDC1A gene, whose high expression in malignant plasma cells is associated with short survival of patients. Using conditional lentiviral vector delivery of DEPDC1A shRNA, we report that DEPDC1A knockdown delayed the growth of human myeloma cell lines (HMCLs), with a block in G2 phase of the cell cycle, p53 phosphorylation and stabilization, and p21(Cip1) accumulation. DEPDC1A knockdown also resulted in increased expression of mature plasma cell markers, including CXCR4, IL6-R and CD38. Thus DEPDC1A could contribute to the plasmablast features of MMCs found in some patients with adverse prognosis, blocking the differentiation of malignant plasma cells and promoting cell cycle.
PLoS ONE 01/2013; 8(4):e62752. · 4.09 Impact Factor
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ABSTRACT: The six-transmembrane epithelial antigen of prostate (STEAP) protein was identified in advanced prostate cancer and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. STEAP1 was described as a suitable antigen for T-cell-based or antibody-based immunotherapy. We have investigated the expression of STEAP1 in 40 human tumor types - brain, epithelial, lymphoid - and in their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. STEAP1 was found significantly overexpressed in 11 cancers. In addition, high STEAP1 expression was associated with poor overall survival in colorectal cancer, diffuse large B cell lymphoma, acute myeloid leukemia and multiple myeloma. Taken together, these data suggest that STEAP1 is a potential therapeutic target for T-cell based immunotherapy or antibody therapy in a large panel of cancers.
Biochemical and Biophysical Research Communications 11/2012; · 2.48 Impact Factor
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ABSTRACT: Gene expression-based scores used to predict risk in cancer frequently include genes coding for DNA replication, repair or recombination. Using two independent cohorts of 206 and 345 previously-untreated patients with Multiple Myeloma (MM), we identified 50 cell cycle-unrelated genes overexpressed in multiple myeloma cells (MMCs) compared to normal human proliferating plasmablasts and non-proliferating bone marrow plasma cells and which have prognostic value for overall survival. Thirty-seven of these 50 myeloma genes (74%) were enriched in genes overexpressed in one of 3 normal human stem cell populations--pluripotent (18), hematopoietic (10) or mesenchymal stem cells (9)--and only three genes were enriched in one of 5 populations of differentiated cells (memory B lymphocytes, T lymphocytes, polymorphonuclear cells, monocytes, osteoclasts). These 37 genes shared by MMCs and adult or pluripotent stem cells were used to build a stem cell score ((SC)score), which proved to be strongly prognostic in the 2 independent cohorts of patients compared to other gene expression-based risk scores or usual clinical scores using multivariate Cox analysis. This finding highlights cell cycle-unrelated prognostic genes shared by myeloma cells and normal stem cells, whose products might be important for normal and malignant stem cell biology.
PLoS ONE 01/2012; 7(7):e42161. · 4.09 Impact Factor
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Alboukadel Kassambara,
Dirk Hose,
Jérôme Moreaux,
Brian A Walker,
Alexei Protopopov,
Thierry Reme,
Franck Pellestor,
Véronique Pantesco,
Anna Jauch,
Gareth Morgan,
Hartmut Goldschmidt,
Bernard Klein
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ABSTRACT: Genetic abnormalities are common in patients with multiple myeloma, and may deregulate gene products involved in tumor survival, proliferation, metabolism and drug resistance. In particular, translocations may result in a high expression of targeted genes (termed spike expression) in tumor cells. We identified spike genes in multiple myeloma cells of patients with newly-diagnosed myeloma and investigated their prognostic value.
Genes with a spike expression in multiple myeloma cells were picked up using box plot probe set signal distribution and two selection filters.
In a cohort of 206 newly diagnosed patients with multiple myeloma, 2587 genes/expressed sequence tags with a spike expression were identified. Some spike genes were associated with some transcription factors such as MAF or MMSET and with known recurrent translocations as expected. Spike genes were not associated with increased DNA copy number and for a majority of them, involved unknown mechanisms. Of spiked genes, 36.7% clustered significantly in 149 out of 862 documented chromosome (sub)bands, of which 53 had prognostic value (35 bad, 18 good). Their prognostic value was summarized with a spike band score that delineated 23.8% of patients with a poor median overall survival (27.4 months versus not reached, P<0.001) using the training cohort of 206 patients. The spike band score was independent of other gene expression profiling-based risk scores, t(4;14), or del17p in an independent validation cohort of 345 patients.
We present a new approach to identify spike genes and their relationship to patients' survival.
Haematologica 11/2011; 97(4):622-30. · 6.42 Impact Factor
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Michel Jourdan,
Anouk Caraux,
Gersende Caron,
Nicolas Robert,
Geneviève Fiol,
Thierry Rème,
Karine Bolloré,
Jean-Pierre Vendrell,
Simon Le Gallou,
Frédéric Mourcin,
John De Vos, Alboukadel Kassambara,
Christophe Duperray,
Dirk Hose,
Thierry Fest,
Karin Tarte,
Bernard Klein
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ABSTRACT: The early steps of differentiation of human B cells into plasma cells are poorly known. We report a transitional population of CD20(low/-)CD38(-) preplasmablasts along differentiation of human memory B cells into plasma cells in vitro. Preplasmablasts lack documented B cell or plasma cell (CD20, CD38, and CD138) markers, express CD30 and IL-6R, and secrete Igs at a weaker level than do plasmablasts or plasma cells. These preplasmablasts further differentiate into CD20(-)CD38(high)CD138(-) plasmablasts and then CD20(-)CD38(high)CD138(+) plasma cells. Preplasmablasts were fully characterized in terms of whole genome transcriptome profiling and phenotype. Preplasmablasts coexpress B and plasma cell transcription factors, but at a reduced level compared with B cells, plasmablasts, or plasma cells. They express the unspliced form of XBP1 mRNA mainly, whereas plasmablasts and plasma cells express essentially the spliced form. An in vivo counterpart (CD19(+)CD20(low/-)CD38(-)IL-6R(+) cells) of in vitro-generated preplasmablasts could be detected in human lymph nodes (0.06% of CD19(+) cells) and tonsils (0.05% of CD19(+) cells). An open access "B to Plasma Cell Atlas," which makes it possible to interrogate gene expression in the process of B cell to plasma cell differentiation, is provided. Taken together, our findings show the existence of a transitional preplasmablast population using an in vitro model of plasma cell generation and of its in vivo counterpart in various lymphoid tissues.
The Journal of Immunology 09/2011; 187(8):3931-41. · 5.79 Impact Factor
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ABSTRACT: The ADAM (a disintegrin and metalloproteinases) and the related ADAMTS (a disintegrin and metalloproteinases with thrombospondin) motifs metalloproteinases are membrane-anchored and secreted proteins exhibiting key roles in mediating cell adhesion, proteolytic shedding, and cell signaling. Dysregulation of these proteins has been observed in some pathologic states, including cancers. Their contribution to multiple myeloma, a plasma-cell neoplasia strongly dependent on bone marrow environment, has been poorly characterized.
We analyzed the expression of genes encoding for these proteins and their inhibitors (tissue inhibitor of metalloproteinases [TIMP], reversion-inducing cysteine-rich protein with kazal motifs) in normal B-cell differentiation, primary malignant plasma cells, human myeloma cell lines, and various bone marrow environment cells. The prognostic value of the expression of these genes was analyzed in two independent series of newly diagnosed patients.
ADAM28 and ADAMTS6 were overexpressed in normal memory B cells, ADAM10 and ADAM19 in plasmablasts, and TIMP1 and TIMP2 in normal bone marrow plasma cells. ADAMTS9 was aberrantly expressed by primary malignant plasma cells and ADAM23 expression was associated with a bad prognosis, its expression being spiked in some primary myeloma cell samples. Bone marrow environment cells displayed distinct expression profiles for genes encoding for ADAMs and their inhibitors. They expressed ADAMTSs genes at a low level, with the exception of bone marrow stromal cells.
This study provides an overview of expression data related to ADAMs and ADAMTSs genes potentially involved in myeloma pathogenesis.
Experimental hematology 02/2011; 39(5):546-557.e8. · 3.11 Impact Factor
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ABSTRACT: Multiple myeloma is characterized by the clonal expansion of malignant plasma cells (multiple myeloma cells [MMCs]), in the bone marrow. Osteolytic bone lesions are detected in 80% of patients because of increased osteoclastic bone resorption and reduced osteoblastic bone formation. MMCs are found closely associated with sites of increased bone resorption. Osteoclasts strongly support MMC survival in vitro. To further elucidate the mechanisms involved in osteoclast/MMC interaction, we have identified 552 genes overexpressed in osteoclasts compared with other bone marrow cell subpopulations. Osteoclasts express specifically genes coding for 4 CCR2-targeting chemokines and genes coding for MMC growth factors. An anti-CCR2 monoclonal antibody blocked osteoclast chemoattractant activity for MMC, and CCR2 chemokines are also MMC growth factors, promoting mitogen-activated protein kinase activation in MMC. An anti-insulin growth factor-1 receptor monoclonal antibody completely blocked the osteoclast-induced survival of MMC suppressing both osteoclast and MMC survival. Specific a proliferation-inducing ligand or IL-6 inhibitors partially blocked osteoclast-induced MMC survival. These data may explain why newly diagnosed patients whose MMC express high levels of CCR2 present numerous bone lesions. This study displays additional mechanisms involved in osteoclast/MMC interaction and suggests using CCR2 and/or insulin growth factor-1 targeting strategies to block this interaction and prevent drug resistance.
Blood 01/2011; 117(4):1280-90. · 9.90 Impact Factor
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ABSTRACT: The transcription factors Oct4 and Sox2 are highly expressed in embryonic stem (ES) cells. In conjunction with Klf4 and c-Myc, their over-expression can induce pluripotency in both mouse and human somatic cells, indicating that these factors are key regulators of the signaling network necessary for ES cell pluripotency. Self-renewal is a hallmark of stem cells and cancer and stemness programming could play an important role in cancer. Therefore we compared the expression of Oct4, Sox2, Klf4 and c-Myc in 40 human tumor types to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. We found significant overexpression of at least 1/4 pluripotency factors Oct4, Sox2, Klf4 or c-Myc in 18 out of the 40 cancer types investigated. Furthermore, within a given tumor category these genes are associated with tumor progression or bad prognosis. A key goal in cancer research is to identify the mechanism by which cancer stem cells arise and self-renew. The overexpression of Oct3/4, Sox2, Klf4 and/or c-Myc could contribute to the pathological self-renewal characteristics of cancer stem cells.
Biochemical and Biophysical Research Communications 04/2009; 383(2):157-62. · 2.48 Impact Factor
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Anne Catherine Sprynski,
Dirk Hose,
Laurent Caillot,
Thierry Réme,
John D Shaughnessy,
Bart Barlogie,
Anja Seckinger,
Jérôme Moreaux,
Michael Hundemer,
Michel Jourdan,
Tobias Meissner,
Anna Jauch,
Karène Mahtouk, Alboukadel Kassambara,
Uta Bertsch,
Jean François Rossi,
Hartmut Goldschmidt,
Bernard Klein
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ABSTRACT: A plethora of myeloma growth factors (MGFs) has been identified, but their relative importance and cooperation have not been determined. We investigated 5 MGFs (interleukin-6 [IL-6], insulin-like growth factor type 1 [IGF-1], hepatocyte growth factor [HGF], HB-epidermal growth factor [HB-EGF], and a proliferation-inducing ligand [APRIL]) in serum-free cultures of human myeloma cell lines (HMCLs). In CD45(-) HMCLs, an autocrine IGF-1 loop promoted autonomous survival whereas CD45(+) HMCLs could not survive without addition of MGFs, mainly IGF-1 and IL-6. IGF-1 was the major one: its activity was abrogated by an IGF-1R inhibitor only, whereas IL-6, HGF, or HB-EGF activity was inhibited by both IGF-1R- and receptor-specific inhibition. APRIL activity was inhibited by its specific inhibitor only. Of the investigated MGFs and their receptors, only expressions of IGF-1R and IL-6R in multiple myeloma cells (MMCs) of patients delineate a group with adverse prognosis. This is mainly explained by a strong association of IGF-1R and IL-6R expression and t(4;14) translocation, but IGF-1R expression without t(4;14) can also have a poor prognosis. Thus, IGF-1-targeted therapy, eventually in combination with anti-IL-6 therapy, could be promising in a subset of patients with MMCs expressing IGF-1R.
Blood 03/2009; 113(19):4614-26. · 9.90 Impact Factor
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Anne Catherine Sprynski,
Dirk Hose,
Laurent Caillot,
Thierry Rème,
John Shaughnessy Jr,
Bart Barlogie,
Anja Seckinger,
Jérôme Moreaux,
Michael Hundemer,
Michel Jourdan,
Tobias Meissner,
Anna Jauch,
Karene Mahtouk, Alboukadel Kassambara,
Uta Bertsch,
Jean-François Rossi,
Hartmut Goldschmidt,
Bernard Klein
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ABSTRACT: A plethora of myeloma growth factors (MGF) has been identified, but their relative importance and cooperation has not been determined. We investigated 5 well-documented MGF (IL-6, IGF-1, HGF, HB-EGF, APRIL) in serum-free cultures of human myeloma cell lines (HMCLs). In all of 3 CD45(-) HMCLs, an autocrine IGF-1 loop promoted autonomous survival. To the contrary, all 5 CD45(+) HMCLs could not survive and required addition of either IL-6 (5/5), IGF-1 (4/5), HGF (1/5), HB-EGF (1/5) or APRIL (1/5). IGF-1 was the major MGF since its activity was abrogated by an IGF-1R inhibitor only, whereas IL-6, HGF or HB-EGF activity was inhibited by both IGF-1R- and receptor-specific inhibition. APRIL activity was inhibited by its specific inhibitor only. Of the investigated MGF and their receptors, only expressions of IGF-1R and IL-6R in myeloma cells (MMC) of patients delineate a group with adverse prognosis. This is mainly explained by a strong association of IGF-1R and IL-6R expression and t(4;14) translocation, but IGF-1R expression in MMC, without t(4;14) can also have a poor prognosis. Thus, IGF-1 targeted therapy - eventually in combination with anti-IL-6 therapy - could be promising in a subset of patients with MMC expressing IGF-1R.
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ABSTRACT: MMSET is expressed ubiquitously in early development and its deletion is associated with the malformation syndrome called Wolf–Hirschhorn syndrome. It is involved in the t(4; 14) (p16; q32) chromosomal translocation, which is the second most common translocation in multiple myeloma (MM) and is associated with the worst prognosis. MMSET expression has been shown to promote cellular adhesion, clonogenic growth and tumorigenicity in multiple myeloma. MMSET expression has been recently shown to increase with ascending tumor proliferation activity in glioblastoma multiforme. These data demonstrate that MMSET could be implicated in tumor emergence and/or progression. Therefore, we compared the expression of MMSET in 40 human tumor types – brain, epithelial, lymphoid – to that of their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. We found significant overexpression of MMSET in 15 cancers compared to their normal counterparts. Furthermore MMSET is associated with tumor aggressiveness or prognosis in many types of these aforementioned cancers.Taken together, these data suggest that MMSET potentially acts as a pathogenic agent in many cancers. The identification of the targets of MMSET and their role in cell growth and survival will be key to understand how MMSET is associated with tumor development.
Biochemical and Biophysical Research Communications.
