Gael Roue - Academia.edu (original) (raw)

Papers by Gael Roue

Cancers, 2019

Alterations in protein-protein and DNA-protein interactions and abnormal chromatin remodeling are... more Alterations in protein-protein and DNA-protein interactions and abnormal chromatin remodeling are a major cause of uncontrolled gene transcription and constitutive activation of critical signaling pathways in cancer cells. Multiple epigenetic regulators are known to be deregulated in several hematologic neoplasms, by somatic mutation, amplification, or deletion, allowing the identification of specific epigenetic signatures, but at the same time providing new therapeutic opportunities. While these vulnerabilities have been traditionally addressed by hypomethylating agents or histone deacetylase inhibitors, pharmacological targeting of bromodomain-containing proteins has recently emerged as a promising approach in a number of lymphoid and myeloid malignancies. Indeed, preclinical and clinical studies highlight the relevance of targeting the bromodomain and extra-terminal (BET) family as an efficient strategy of target transcription irrespective of the presence of epigenetic mutations....

Cancer Research

The small GTPase Ras homolog family member A (RHOA) is one of the most extensively investigated m... more The small GTPase Ras homolog family member A (RHOA) is one of the most extensively investigated members of the Rho GTPase family, that acts as a molecular switch controlling a wide variety of signal transduction pathways. Although RHOA has long been implicated in malignant transformation in solid tumors, recent evidences have demonstrated its tumor suppressor activity in different subgroups of B-cell non-Hodgkin lymphoma (B-NHL). Here, using a panel of 11 cell lines covering the most common and/or aggressive B-NHL subtypes, we observed that the lowest mRNA and protein levels of RHOA are found in mantle cell lymphoma (MCL), the most aggressive entity with a median overall survival of 5-7 years. Depletion of RHOA expression and activity was carried out in the two RHOA+ MCL cell lines, REC-1 and Z-138, by CRISPR/Cas9-mediated gene edition followed by RHOA pulldown activation assay. In RHOA knockout (KO) subclones, cell proliferation was increased by 40%, in association with a 10-fold i...

Cancer Research, 2013

Phosphatidylinositol-3-kinase (PI3K) pathway is a key component of many cancers survival. Particu... more Phosphatidylinositol-3-kinase (PI3K) pathway is a key component of many cancers survival. Particularly, PI3K is constitutively activated in chronic lymphocytic leukemia (CLL) due to microenvironment signals, including stromal cell interaction, CXCR4 activation and B-cell receptor (BCR) triggering. Because of the importance of PI3K for CLL-microenvironment cross-talk and chemotherapy resistance, we investigated the activity of the NVP-BKM120, an orally available pan class I PI3K inhibitor. Here, we show that NVP-BKM120 promoted mitochondrial apoptosis in primary CLL cells independently of common prognostic markers. At the molecular level, NVP-BKM120 blocked PI3K signalling, resulting in decreased phosphorylation of Akt and FoxO3a while downregulating Mcl-1 and inducing Bim. Importantly, selective knockdown of BIM rescued cells from NVP-BKM120-induced apoptosis. Moreover, NVP-BKM120 enhanced the activity of the BH3-mimetic ABT263 in CLL cells, leading to synergistic apoptosis inductio...

Frontiers in Genetics, 2019

In the last 10 years, major advances have been made in the diagnosis and development of selective... more In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field.

Blood

Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its... more Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its overexpression has been linked with aggressive tumour progression. Here, we show that Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphomas. PARP-1 and PARP-2 catalyse the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA-strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphomas, while PARP-1-deficiency accelerates lymphomagenesis in the Em-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in pre-leukemic Em-Myc B cells resulting i...

Oncoscience

Esteve-Arenys et al. This is an open-access article distributed under the terms of the Creative C... more Esteve-Arenys et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Experimental and Molecular Therapeutics

Blood

Mantle cell lymphoma (MCL) is an aggressive B lymphoid neoplasm with a mature B-cell phenotype an... more Mantle cell lymphoma (MCL) is an aggressive B lymphoid neoplasm with a mature B-cell phenotype and genetically characterized by the t(11;14)(q13;q32) leading to cyclin D1 overexpression with the consequent deregulation of cell cycle at the G1-S checkpoint. MCL cells present a constitutive activation of the NF-kappaB pathway which leads to the overexpression of several anti-apoptotic regulators. Recently, MCL cells have been shown to express high levels of the chaperone heat shock protein of 90 kDa (HSP90) and to respond well to the ansamycin derivative 17-AAG, an HSP90 inhibitor. We have analyzed the sensitivity to the novel, highly soluble, 17-AAG derivative IPI-504 (Infinity Pharmaceuticals) on a panel of eleven human MCL cell lines and primary cells from MCL patients, which differ in their p53-dependent pathway status, growth characteristics and sensitivity to cytotoxic drugs. We observed that IPI-504 heterogeneously exerted cytostatic effect among MCL samples, with IC50 ranging ...

Blood

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive prege... more Mantle cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive pregerminal center cells with a mature B-cell phenotype and an aggressive course. MCL cells are characterized by the chromosomal translocation t(11;14)(q13;q32) which results in cyclin D1 overexpression, and also present a constitutive activation of the NFkB pathway which leads to the overexpression of several anti-apoptotic regulators. As a consequence, these cells poorly respond to common chemotherapeutic agents acting via the intrinsic mitochondrial pathway. However, recent results indicate that proteasome inhibition represents a promising way to initiate or to potentiate apoptotic cell death in MCL cells, mainly by regulating the levels of several members of the Bcl-2 family implicated in the mitochondrial apoptotic pathway. On the other hand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent activator of the extrinsic cell death pathway and has been shown to exe...

Blood

Mantle cell lymphoma (MCL) is a lymphoid malignancy derived from a subset of mature B-cells with ... more Mantle cell lymphoma (MCL) is a lymphoid malignancy derived from a subset of mature B-cells with coexpression of CD5 and the chromosomal translocation t(11;14)(q13;q32). MCL patients present an aggressive clinical course and poor response to conventional chemotherapy due to either rapid relapse after an initial response or primary resistance to drugs. Thus, there is currently a strong effort to develop compounds that target novel biological pathways. In addition, MCL cells overexpress the antiapoptotic proteins Bcl-2, Bcl-XL and Mcl-1. The dysregulated Bcl-2 pathway represents an important target for a new-mechanism therapeutic approach. In this context, the pan-Bcl-2 inhibitor GX15-070 that belongs to a new family of compounds which mimic BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members and consequently eliciting Bax and Bak dependent cytotoxicity. GX15-070 is currently being evaluated in Phase I clinical trials. GX15-070 induced apoptosis in vitro in primary ce...

Blood

According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute mye... more According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response ...

Blood

Introduction Terminal erythroid differentiation (TED) follows a doubling pattern of maturation in... more Introduction Terminal erythroid differentiation (TED) follows a doubling pattern of maturation in each erythroid stage from proerythroblast to orthochromatic erythroblast. Recently, it has been shown by flow cytometry that erythroid differentiation is profoundly abnormal across all MDS subtypes and that the absence of quantifiable cells undergoing TED by well-defined cell surface markers is strongly associated with inferior overall survival (OS). Analysis of TED is not easy to perform and, notably, TED in MDS has not been systematically assessed by morphology, the gold standard analysis for MDS diagnosis. Against this background, we studied the pattern of TED maturation by conventional microscopy and compared clinical and prognostic characteristics between MDS patients with normal and abnormal TED. Methods Cytological analysis of erythroid cells was assessed in bone marrow smears in 500-cell differential count from patients diagnosed with MDS from 2011 to 2018 at our institution. TE...

Blood

Introduction Patients diagnosed with AML with NPM1mutation (NPM1mut AML) included in the European... more Introduction Patients diagnosed with AML with NPM1mutation (NPM1mut AML) included in the European LeukemiaNet favorable genetic risk category (ELNfav, i.e., without FLT3-ITD or with a low allelic burden FLT3-ITD comutation [FLT3-ITD/FLT3wt <0.5; FLT3-ITDLOW]) do not benefit from an allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). However, a significant proportion of these patients fail to frontline chemotherapy and require salvage therapy. Persistence or detection of MRD after post-CR treatment is associated with a high relapse risk and worse prognosis. With this background, the cooperative group CETLAM proposed an early therapeutic intervention in CETLAM-2012 protocol for patients with ELNfavNPM1mut AML patients not achieving a sustained MRD clearance after consolidation therapy, defined as molecular failure (MF). Herein we analyzed the outcome and predictive risk factors of MF. Methods All patients diagnosed with ELNfav NPM1mut AML treated accor...

Blood

Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for pro... more Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for proliferation and survival. In the lymphoid follicle, FL cells are surrounded by follicular dendrytic cells (FDCs) that function as antigen presenting cells delivering survival and proliferation signaling. FDCs together with macrophages are associated to poor FL survival. Our aim was to uncover the signaling pathways underlying FL-FDC crosstalk and its validation as new targets for therapy using specific inhibitors. Global gene expression profiling of FL-FDC co-cultures yield a marked modulation of FL transcriptome by FDCs. The Principal Component Analysis (PCA) showed that HK-cocultured FL cells clustered together,independently of the patient origin. Then, pathways assignmentwas performed by DAVID and GSEA softwares, both of themuncovering an overrepresentation on genes related toangiogenesis. In the DAVID analysis, we found significant(False Discovery Rate (FDR)<5%,) angiogenesis–relat...

Blood

3734 Poster Board III-670 Introduction The endoplasmic reticulum (ER) stress response is an adapt... more 3734 Poster Board III-670 Introduction The endoplasmic reticulum (ER) stress response is an adaptive signaling pathway that controls cell survival. The activation of the transcription factor Xbp1 is a main event in this response and we have previously shown that Xbp1 activation in DLBCL is associated with aggressive clinical course (Balagué et al. Am J Pathol 2009, 174(6):2337-46). GRP78/Bip is a molecular chaperone that senses ER homeostasis and initiates the ER stress response. The expression of GRP78/Bip in DLBCL has never been addressed before. DLBCL patients are treated with standard doxorubicin-based chemotherapy such as CHOP. Since the introduction of rituximab, no other therapies have shown greater benefit in these patients. The ER stress response may be altered by conventional chemotherapy and it is well known that proteasome inhibition with bortezomib disrupts this response in myeloma. Whether Bip is affected in DLBCL treated with R-CHOP or bortezomib is unknown. Recent e...

Blood

Daratumumab (DARA) is a human CD38 antibody with broad-spectrum killing activity. DARA induces ki... more Daratumumab (DARA) is a human CD38 antibody with broad-spectrum killing activity. DARA induces killing of tumor cells, mainly via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) (de Weers M, J Immunol 2011). DARA is currently being evaluated in phase I/II clinical trials in patients with multiple myeloma. In these clinical studies the adverse events have been manageable and marked reductions in paraprotein and bone marrow plasma cells have been observed. We have previously reported (Blood (ASH annual meeting abstracts). Nov 2012, 120 (21): 3935) that DARA induces cytotoxic activity in vitro via ADCC in primary cells and cell lines from Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL) and Chronic Lymphoctic Leukemia (CLL). CDC induction was low, which is associated to high expression of the complement inhibitors and reduced number of CD38 molecules per cell in these indications. This suggests a threshold for CD38-targeted CDC lysis...

Blood

3880 The two TNF family proteins, B-cell activating factor [BAFF] and a proliferation-inducing li... more 3880 The two TNF family proteins, B-cell activating factor [BAFF] and a proliferation-inducing ligand [APRIL], and their three receptors, transmembrane activator and CAML interactor [TACI], B-cell maturation antigen [BCMA], and BAFF receptor [BAFF-R] are critical regulators of normal B-cell development and survival. In CLL, both proteins can rescue CLL cells from apoptosis as shown in in vitro studies. We and others have previously shown that patients with CLL and other B-cell chronic lymphoproliferative disorders show abnormal BAFF and APRIL serum levels. Additionally, a few reports indicate that CLL cells can express BAFF and APRIL receptors. Nevertheless, there is no a meaningful and comparative analysis of BAFF-R, TACI and BCMA levels in CLL. We therefore quantitatively assessed BAFF-R, TACI and BCMA on B-cells from patients with CLL and healthy controls. The expression of BAFF-R, TACI and BCMA was analyzed by flow cytometry in purified peripheral blood B cells from 42 patients ...

Blood

Introduction: Even with the use of novel drugs in patients with multiple myeloma (MM), relapse re... more Introduction: Even with the use of novel drugs in patients with multiple myeloma (MM), relapse remains a challenge. Anti-myeloma activity of the immunomodulatory drug lenalidomide has been shown to rely on cereblon E3 ubiquitin ligase complex-dependent degradation of IRF4 and Ikaros, both required for MM cell survival. As these two factors are involved in the regulation of MYC transcription, we wanted to evaluate the effect of combining a MYC-interfering therapy with a lenalidomide and dexamethasone (Len/Dex) regimen. Methods: Seven MM cell lines (ARP-1, JJN-3, U266, MM.1S, MM.1R, RMPI-8226 and KMM.1) were exposed to the BET bromodomain inhibitor CPI203 in the presence or absence of a standard dose of Len/Dex, followed by MTT assay, flow cytometry, western blot and gene expression arrays. Significant gene signatures were identified using gene set enrichment analysis (GSEA) v2.0 (Broad Institute at MIT). These results were validated in primary cells derived from bone marrow of 9 pati...

Cancers, 2019

Alterations in protein-protein and DNA-protein interactions and abnormal chromatin remodeling are... more Alterations in protein-protein and DNA-protein interactions and abnormal chromatin remodeling are a major cause of uncontrolled gene transcription and constitutive activation of critical signaling pathways in cancer cells. Multiple epigenetic regulators are known to be deregulated in several hematologic neoplasms, by somatic mutation, amplification, or deletion, allowing the identification of specific epigenetic signatures, but at the same time providing new therapeutic opportunities. While these vulnerabilities have been traditionally addressed by hypomethylating agents or histone deacetylase inhibitors, pharmacological targeting of bromodomain-containing proteins has recently emerged as a promising approach in a number of lymphoid and myeloid malignancies. Indeed, preclinical and clinical studies highlight the relevance of targeting the bromodomain and extra-terminal (BET) family as an efficient strategy of target transcription irrespective of the presence of epigenetic mutations....

Cancer Research

The small GTPase Ras homolog family member A (RHOA) is one of the most extensively investigated m... more The small GTPase Ras homolog family member A (RHOA) is one of the most extensively investigated members of the Rho GTPase family, that acts as a molecular switch controlling a wide variety of signal transduction pathways. Although RHOA has long been implicated in malignant transformation in solid tumors, recent evidences have demonstrated its tumor suppressor activity in different subgroups of B-cell non-Hodgkin lymphoma (B-NHL). Here, using a panel of 11 cell lines covering the most common and/or aggressive B-NHL subtypes, we observed that the lowest mRNA and protein levels of RHOA are found in mantle cell lymphoma (MCL), the most aggressive entity with a median overall survival of 5-7 years. Depletion of RHOA expression and activity was carried out in the two RHOA+ MCL cell lines, REC-1 and Z-138, by CRISPR/Cas9-mediated gene edition followed by RHOA pulldown activation assay. In RHOA knockout (KO) subclones, cell proliferation was increased by 40%, in association with a 10-fold i...

Cancer Research, 2013

Phosphatidylinositol-3-kinase (PI3K) pathway is a key component of many cancers survival. Particu... more Phosphatidylinositol-3-kinase (PI3K) pathway is a key component of many cancers survival. Particularly, PI3K is constitutively activated in chronic lymphocytic leukemia (CLL) due to microenvironment signals, including stromal cell interaction, CXCR4 activation and B-cell receptor (BCR) triggering. Because of the importance of PI3K for CLL-microenvironment cross-talk and chemotherapy resistance, we investigated the activity of the NVP-BKM120, an orally available pan class I PI3K inhibitor. Here, we show that NVP-BKM120 promoted mitochondrial apoptosis in primary CLL cells independently of common prognostic markers. At the molecular level, NVP-BKM120 blocked PI3K signalling, resulting in decreased phosphorylation of Akt and FoxO3a while downregulating Mcl-1 and inducing Bim. Importantly, selective knockdown of BIM rescued cells from NVP-BKM120-induced apoptosis. Moreover, NVP-BKM120 enhanced the activity of the BH3-mimetic ABT263 in CLL cells, leading to synergistic apoptosis inductio...

Frontiers in Genetics, 2019

In the last 10 years, major advances have been made in the diagnosis and development of selective... more In the last 10 years, major advances have been made in the diagnosis and development of selective therapies for several blood cancers, including B-cell non-Hodgkin lymphoma (B-NHL), a heterogeneous group of malignancies arising from the mature B lymphocyte compartment. However, most of these entities remain incurable and current treatments are associated with variable efficacy, several adverse events, and frequent relapses. Thus, new diagnostic paradigms and novel therapeutic options are required to improve the prognosis of patients with B-NHL. With the recent deciphering of the mutational landscapes of B-cell disorders by high-throughput sequencing, it came out that different epigenetic deregulations might drive and/or promote B lymphomagenesis. Consistently, over the last decade, numerous epigenetic drugs (or epidrugs) have emerged in the clinical management of B-NHL patients. In this review, we will present an overview of the most relevant epidrugs tested and/or used so far for the treatment of different subtypes of B-NHL, from first-generation epigenetic therapies like histone acetyl transferases (HDACs) or DNA-methyl transferases (DNMTs) inhibitors to new agents showing selectivity for proteins that are mutated, translocated, and/or overexpressed in these diseases, including EZH2, BET, and PRMT. We will dissect the mechanisms of action of these epigenetic inhibitors, as well as the molecular processes underlying their lack of efficacy in refractory patients. This review will also provide a summary of the latest strategies being employed in preclinical and clinical settings, and will point out the most promising lines of investigation in the field.

Blood

Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its... more Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its overexpression has been linked with aggressive tumour progression. Here, we show that Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphomas. PARP-1 and PARP-2 catalyse the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA-strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphomas, while PARP-1-deficiency accelerates lymphomagenesis in the Em-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in pre-leukemic Em-Myc B cells resulting i...

Oncoscience

Esteve-Arenys et al. This is an open-access article distributed under the terms of the Creative C... more Esteve-Arenys et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Experimental and Molecular Therapeutics

Blood

Mantle cell lymphoma (MCL) is an aggressive B lymphoid neoplasm with a mature B-cell phenotype an... more Mantle cell lymphoma (MCL) is an aggressive B lymphoid neoplasm with a mature B-cell phenotype and genetically characterized by the t(11;14)(q13;q32) leading to cyclin D1 overexpression with the consequent deregulation of cell cycle at the G1-S checkpoint. MCL cells present a constitutive activation of the NF-kappaB pathway which leads to the overexpression of several anti-apoptotic regulators. Recently, MCL cells have been shown to express high levels of the chaperone heat shock protein of 90 kDa (HSP90) and to respond well to the ansamycin derivative 17-AAG, an HSP90 inhibitor. We have analyzed the sensitivity to the novel, highly soluble, 17-AAG derivative IPI-504 (Infinity Pharmaceuticals) on a panel of eleven human MCL cell lines and primary cells from MCL patients, which differ in their p53-dependent pathway status, growth characteristics and sensitivity to cytotoxic drugs. We observed that IPI-504 heterogeneously exerted cytostatic effect among MCL samples, with IC50 ranging ...

Blood

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive prege... more Mantle cell lymphoma (MCL) is a lymphoproliferative disorder derived from a subset of naive pregerminal center cells with a mature B-cell phenotype and an aggressive course. MCL cells are characterized by the chromosomal translocation t(11;14)(q13;q32) which results in cyclin D1 overexpression, and also present a constitutive activation of the NFkB pathway which leads to the overexpression of several anti-apoptotic regulators. As a consequence, these cells poorly respond to common chemotherapeutic agents acting via the intrinsic mitochondrial pathway. However, recent results indicate that proteasome inhibition represents a promising way to initiate or to potentiate apoptotic cell death in MCL cells, mainly by regulating the levels of several members of the Bcl-2 family implicated in the mitochondrial apoptotic pathway. On the other hand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent activator of the extrinsic cell death pathway and has been shown to exe...

Blood

Mantle cell lymphoma (MCL) is a lymphoid malignancy derived from a subset of mature B-cells with ... more Mantle cell lymphoma (MCL) is a lymphoid malignancy derived from a subset of mature B-cells with coexpression of CD5 and the chromosomal translocation t(11;14)(q13;q32). MCL patients present an aggressive clinical course and poor response to conventional chemotherapy due to either rapid relapse after an initial response or primary resistance to drugs. Thus, there is currently a strong effort to develop compounds that target novel biological pathways. In addition, MCL cells overexpress the antiapoptotic proteins Bcl-2, Bcl-XL and Mcl-1. The dysregulated Bcl-2 pathway represents an important target for a new-mechanism therapeutic approach. In this context, the pan-Bcl-2 inhibitor GX15-070 that belongs to a new family of compounds which mimic BH3-only proteins by binding to multiple antiapoptotic Bcl-2 members and consequently eliciting Bax and Bak dependent cytotoxicity. GX15-070 is currently being evaluated in Phase I clinical trials. GX15-070 induced apoptosis in vitro in primary ce...

Blood

According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute mye... more According to the 2016 WHO classification, AML-MRC encompasses an heterogeneous group of acute myeloid leukemias (AML) comprising: AML emerged from a previous myelodysplastic syndrome (MDS) or myeloproliferative /myelodysplastic disease (group 1), AML with MDS-defining cytogenetic abnormalities (group 2), or acute myeloid leukemia (AML) with dysplasia in at least 2 cell lineages without the above mentioned (group 3). In spite that AML-MRC has been considered a high-risk entity with poor prognosis, little is known on the relationship of clinical and biological characteristics with outcomes in these three groups. The aim of this study was to describe the clinical and biological characteristics of patients with AML-MRC and analyze their prognostic variables and outcomes. We retrospectively analyzed AML-MRC cases diagnosed between January-2009 and December- 2018 in two institutions. Descriptive variables were studied to compare the three AML-MRC groups. AML cytogenetic risk and response ...

Blood

Introduction Terminal erythroid differentiation (TED) follows a doubling pattern of maturation in... more Introduction Terminal erythroid differentiation (TED) follows a doubling pattern of maturation in each erythroid stage from proerythroblast to orthochromatic erythroblast. Recently, it has been shown by flow cytometry that erythroid differentiation is profoundly abnormal across all MDS subtypes and that the absence of quantifiable cells undergoing TED by well-defined cell surface markers is strongly associated with inferior overall survival (OS). Analysis of TED is not easy to perform and, notably, TED in MDS has not been systematically assessed by morphology, the gold standard analysis for MDS diagnosis. Against this background, we studied the pattern of TED maturation by conventional microscopy and compared clinical and prognostic characteristics between MDS patients with normal and abnormal TED. Methods Cytological analysis of erythroid cells was assessed in bone marrow smears in 500-cell differential count from patients diagnosed with MDS from 2011 to 2018 at our institution. TE...

Blood

Introduction Patients diagnosed with AML with NPM1mutation (NPM1mut AML) included in the European... more Introduction Patients diagnosed with AML with NPM1mutation (NPM1mut AML) included in the European LeukemiaNet favorable genetic risk category (ELNfav, i.e., without FLT3-ITD or with a low allelic burden FLT3-ITD comutation [FLT3-ITD/FLT3wt <0.5; FLT3-ITDLOW]) do not benefit from an allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). However, a significant proportion of these patients fail to frontline chemotherapy and require salvage therapy. Persistence or detection of MRD after post-CR treatment is associated with a high relapse risk and worse prognosis. With this background, the cooperative group CETLAM proposed an early therapeutic intervention in CETLAM-2012 protocol for patients with ELNfavNPM1mut AML patients not achieving a sustained MRD clearance after consolidation therapy, defined as molecular failure (MF). Herein we analyzed the outcome and predictive risk factors of MF. Methods All patients diagnosed with ELNfav NPM1mut AML treated accor...

Blood

Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for pro... more Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for proliferation and survival. In the lymphoid follicle, FL cells are surrounded by follicular dendrytic cells (FDCs) that function as antigen presenting cells delivering survival and proliferation signaling. FDCs together with macrophages are associated to poor FL survival. Our aim was to uncover the signaling pathways underlying FL-FDC crosstalk and its validation as new targets for therapy using specific inhibitors. Global gene expression profiling of FL-FDC co-cultures yield a marked modulation of FL transcriptome by FDCs. The Principal Component Analysis (PCA) showed that HK-cocultured FL cells clustered together,independently of the patient origin. Then, pathways assignmentwas performed by DAVID and GSEA softwares, both of themuncovering an overrepresentation on genes related toangiogenesis. In the DAVID analysis, we found significant(False Discovery Rate (FDR)<5%,) angiogenesis–relat...

Blood

3734 Poster Board III-670 Introduction The endoplasmic reticulum (ER) stress response is an adapt... more 3734 Poster Board III-670 Introduction The endoplasmic reticulum (ER) stress response is an adaptive signaling pathway that controls cell survival. The activation of the transcription factor Xbp1 is a main event in this response and we have previously shown that Xbp1 activation in DLBCL is associated with aggressive clinical course (Balagué et al. Am J Pathol 2009, 174(6):2337-46). GRP78/Bip is a molecular chaperone that senses ER homeostasis and initiates the ER stress response. The expression of GRP78/Bip in DLBCL has never been addressed before. DLBCL patients are treated with standard doxorubicin-based chemotherapy such as CHOP. Since the introduction of rituximab, no other therapies have shown greater benefit in these patients. The ER stress response may be altered by conventional chemotherapy and it is well known that proteasome inhibition with bortezomib disrupts this response in myeloma. Whether Bip is affected in DLBCL treated with R-CHOP or bortezomib is unknown. Recent e...

Blood

Daratumumab (DARA) is a human CD38 antibody with broad-spectrum killing activity. DARA induces ki... more Daratumumab (DARA) is a human CD38 antibody with broad-spectrum killing activity. DARA induces killing of tumor cells, mainly via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) (de Weers M, J Immunol 2011). DARA is currently being evaluated in phase I/II clinical trials in patients with multiple myeloma. In these clinical studies the adverse events have been manageable and marked reductions in paraprotein and bone marrow plasma cells have been observed. We have previously reported (Blood (ASH annual meeting abstracts). Nov 2012, 120 (21): 3935) that DARA induces cytotoxic activity in vitro via ADCC in primary cells and cell lines from Mantle Cell Lymphoma (MCL), Follicular Lymphoma (FL) and Chronic Lymphoctic Leukemia (CLL). CDC induction was low, which is associated to high expression of the complement inhibitors and reduced number of CD38 molecules per cell in these indications. This suggests a threshold for CD38-targeted CDC lysis...

Blood

3880 The two TNF family proteins, B-cell activating factor [BAFF] and a proliferation-inducing li... more 3880 The two TNF family proteins, B-cell activating factor [BAFF] and a proliferation-inducing ligand [APRIL], and their three receptors, transmembrane activator and CAML interactor [TACI], B-cell maturation antigen [BCMA], and BAFF receptor [BAFF-R] are critical regulators of normal B-cell development and survival. In CLL, both proteins can rescue CLL cells from apoptosis as shown in in vitro studies. We and others have previously shown that patients with CLL and other B-cell chronic lymphoproliferative disorders show abnormal BAFF and APRIL serum levels. Additionally, a few reports indicate that CLL cells can express BAFF and APRIL receptors. Nevertheless, there is no a meaningful and comparative analysis of BAFF-R, TACI and BCMA levels in CLL. We therefore quantitatively assessed BAFF-R, TACI and BCMA on B-cells from patients with CLL and healthy controls. The expression of BAFF-R, TACI and BCMA was analyzed by flow cytometry in purified peripheral blood B cells from 42 patients ...

Blood

Introduction: Even with the use of novel drugs in patients with multiple myeloma (MM), relapse re... more Introduction: Even with the use of novel drugs in patients with multiple myeloma (MM), relapse remains a challenge. Anti-myeloma activity of the immunomodulatory drug lenalidomide has been shown to rely on cereblon E3 ubiquitin ligase complex-dependent degradation of IRF4 and Ikaros, both required for MM cell survival. As these two factors are involved in the regulation of MYC transcription, we wanted to evaluate the effect of combining a MYC-interfering therapy with a lenalidomide and dexamethasone (Len/Dex) regimen. Methods: Seven MM cell lines (ARP-1, JJN-3, U266, MM.1S, MM.1R, RMPI-8226 and KMM.1) were exposed to the BET bromodomain inhibitor CPI203 in the presence or absence of a standard dose of Len/Dex, followed by MTT assay, flow cytometry, western blot and gene expression arrays. Significant gene signatures were identified using gene set enrichment analysis (GSEA) v2.0 (Broad Institute at MIT). These results were validated in primary cells derived from bone marrow of 9 pati...