Thiollier C.,French Institute of Health and Medical Research |
Thiollier C.,University Paris Diderot |
Thiollier C.,Institute Gustave Roussy |
Lopez C.K.,French Institute of Health and Medical Research |
And 53 more authors.
Journal of Experimental Medicine | Year: 2012
Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors. © 2012 Thiollier et al.
Bluteau D.,French Institute of Health and Medical Research |
Bluteau D.,University Paris - Sud |
Bluteau D.,Institute Gustave Roussy |
Gilles L.,French Institute of Health and Medical Research |
And 38 more authors.
Blood | Year: 2011
RUNX1 encodes a DNA-binding α subunit of the core-binding factor, a heterodimeric transcription factor. RUNX1 is a master regulatory gene in hematopoiesis and its disruption is one of the most common aberrations in acute leukemia. Inactivating or dominant-negative mutations in the RUNX1 gene have been also identified in pedigrees of familial platelet disorders with a variable propensity to develop acute myeloid leukemia (FPD/AML). We performed analysis of hematopoiesis from 2 FPD/AML pedigrees with 2 distinct RUNX1 germline mutations, that is, the R139X in a pedigree without AML and the R174Q mutation in a pedigree with AML. Both mutations induced a marked increase in the clonogenic potential of immature CD34 + CD38 - progenitors, with some selfrenewal capacities observed only for R174Q mutation. This increased proliferation correlated with reduction in the expression of NR4A3, a gene previously implicated in leukemia development. We demonstrated that NR4A3 was a direct target of RUNX1 and that restoration of NR4A3 expression partially reduced the clonogenic potential of patient progenitors. We propose that the down-regulation of NR4A3 in RUNX1-mutated hematopoietic progenitors leads to an increase in the pool of cells susceptible to be hit by secondary leukemic genetic events. © 2011 by The American Society of Hematology.
Manchev V.T.,University Paris - Sud |
Manchev V.T.,University Paris Diderot |
Manchev V.T.,French Institute of Health and Medical Research |
Hilpert M.,University Paris - Sud |
And 26 more authors.
Blood | Year: 2014
Macrothrombocytopenias are the most important subgroup of inherited thrombocytopenias. This subgroup is particularly heterogeneous because the affected genes are involved in various functions such as cell signaling, cytoskeleton organization, and gene expression. Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients. Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients. Exome sequencing identified a c.222C>G mutation (missense p.74Ile>Met) in PRKACG, a gene encoding the γ-catalytic subunit of the cyclic adenosine monophosphate-dependent protein kinase, the mutated allele cosegregating with the macrothrombocytopenia. We demonstrate that the p.74Ile>Met PRKACG mutation is associated with a marked defect in proplatelet formation and a low level in filamin A in megakaryocytes (MKs). The defect in proplatelet formation was rescued in vitro by lentiviral vector-mediated overexpression of wild-type PRKACG in patien tMKs. We thus conclude that PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy. © 2014 by The American Society of Hematology.
Besancenot R.,French Institute of Health and Medical Research |
Besancenot R.,Institute Gustave Roussy |
Besancenot R.,Integrated Research Cancer Institute in Villejuif |
Besancenot R.,University Paris Diderot |
And 41 more authors.
Blood | Year: 2014
Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2- or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocytic proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote a paradoxical thrombocytosis when used at suboptimal doses. © 2014 by The American Society of Hematology.
Bonneau C.,University of Versailles |
Gurard-Levin Z.A.,University Pierre and Marie Curie |
Andre F.,Integrated Research Cancer Institute in Villejuif |
Pusztai L.,Yale University |
Rouzier R.,University of Versailles
Anticancer Research | Year: 2015
Background/Aim: Predictive markers for response to chemotherapy are required in breast cancer. The Tau protein is a microtubule-associated protein variably expressed in breast cancer. The objective of our study was to describe drug resistance induced by the tau protein, and its predictive and prognostic value in breast cancer. Materials and Methods: Medline and PubMed databases were searched in April 2015 for terms "tau protein", "breast cancer", "chemotherapy sensitivity", "biomarker" and "taxane resistance". Results: In vitro, tau protein competes with taxane for controlling microtubule dynamic and loss of tau expression may render microtubules more vulnerable to the effects of taxanes. High tau protein expression was associated with better prognosis, even after adjustment for grade, hormone receptor and human epidermal growth factor receptor-2 expression, nodal status. The predictive value of the tau protein for sensitivity to taxane is discordant despite there being a trend for an association between low tau expression and increased response rate. Conclusion: Tau protein expression is insufficient for identifying a subset of patients with carcinomas that may benefit more from chemotherapy.
PubMed | Yale University, Integrated Research Cancer Institute in Villejuif, University of Versailles and University Pierre and Marie Curie
Type: Journal Article | Journal: Anticancer research | Year: 2015
Predictive markers for response to chemotherapy are required in breast cancer. The Tau protein is a microtubule-associated protein variably expressed in breast cancer. The objective of our study was to describe drug resistance induced by the tau protein, and its predictive and prognostic value in breast cancer.Medline and PubMed databases were searched in April 2015 for terms tau protein, breast cancer, chemotherapy sensitivity, biomarker and taxane resistance.In vitro, tau protein competes with taxane for controlling microtubule dynamic and loss of tau expression may render microtubules more vulnerable to the effects of taxanes. High tau protein expression was associated with better prognosis, even after adjustment for grade, hormone receptor and human epidermal growth factor receptor-2 expression, nodal status. The predictive value of the tau protein for sensitivity to taxane is discordant despite there being a trend for an association between low tau expression and increased response rate.Tau protein expression is insufficient for identifying a subset of patients with carcinomas that may benefit more from chemotherapy.
Hage F.E.,Holy Spirit University of Kaslik |
Durgeau A.,Integrated Research Cancer Institute in Villejuif |
Mami-Chouaib F.,Integrated Research Cancer Institute in Villejuif
Annals of the New York Academy of Sciences | Year: 2013
We identified that the antigen preprocalcitonin (ppCT) is recognized on a human lung carcinoma by a cytotoxic T lymphocyte clone derived from autologous tumor-infiltrating lymphocytes. The antigenic peptide ppCT16-25 is encoded by the gene calcitonin-related polypeptide alpha (CALCA), which codes for CT and is overexpressed in several lung carcinomas compared with normal tissues. The ppCT peptide is derived from the C-terminal region of the signal peptide and is processed independently of proteasomes and the transporter associated with antigen processing (TAP)1/TAP2 heterodimeric complexes. Instead, processing occurs within the endoplasmic reticulum by a novel mechanism involving signal pepsidase (SP) and signal peptide peptidase (SPP). Although lung cancer cells bearing the ppCT16-25 epitope displayed low levels of TAP, restoration of TAP expression by interferon (IFN)-γ treatment or by TAP1/TAP2 gene transfer inhibited ppCT antigen presentation. Thus, the ppCT16-25 human tumor epitope requires low TAP expression for efficient presentation. These results indicate that emerging SP-generated peptides represent alternative T cell targets that permit cytotoxic T lymphocytes to destroy TAP-impaired tumors, a process that helps to overcome tumor escape from CD8+ T cell immunity. Additionally, our data suggest that ppCT is a promising candidate for cancer immunotherapy. © 2013 The New York Academy of Sciences.