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Valérie Ugo

Publications and source records attributed to Valérie Ugo.

9 recordsLinked to original sources
PubMed2006

Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells.

The biologic hallmark of polycythemia vera (PV) is the formation of endogenous erythroid colonies (EECs) with an erythropoietin-independent differentiation. Recently, it has been shown that an activating mutation of JAK2 (V617F) was at the origin of PV. In this work, we studied whether the STAT5/Bcl-xL pathway could be responsible for EEC formation. A constitutively active form of STAT5 was transduced into human erythroid progenitors and induced an erythropoietin-independent terminal differentiation and EEC formation. Furthermore, Bcl-xL overexpression in erythroid progenitors was also able to induce erythroid colonies despite the absence of erythropoietin. Conversely, siRNA-mediated STAT5 and Bcl-xL knock-down in human erythroid progenitors inhibited colony-forming unit-erythroid (CFU-E) formation in the presence of Epo. Altogether, these results demonstrate that a sustained level of the sole Bcl-xL is capable of giving rise to Epo-independent erythroid colony formation and suggest that, in PV patients, JAK2(V617F) may induce EEC via the STAT5/Bcl-xL pathway.

Cell Differentiation↗
PubMed2006

Deciphering leukemic B-cell chronic lymphoproliferative disorders.

Diagnosis of leukemic B-cell chronic lymphoproliferative disorders (B-CLPD) is a frequent challenge in hematology. In this multicentric study, we prospectively studied 165 new consecutive leukemic patients with B-CLPD selected on the basis of Royal Marsden Hospital scoring system < or =3. The primary aim of the study was to try to decipher the atypical cases and identify homogenous subgroups. Overall, morphological examination contributed to diagnosis in only 20% cases, all of them CD5 negative. Thirty additional cases were CD5 negative suggestive of leukemic marginal zone lymphoma in most cases. The significantly poorer survival of the 26 cyclin D1 positive cases justifies recommending its systematic determination among atypical B-CLPD. CD20 expression segregated clearly two subgroups among CD5 positive cyclin D1 negative B-CLPD. The 17 patients with the CD20 dim profile represent a homogeneous subgroup very close to typical B-cell chronic lymphocytic leukemia (B-CLL) on morphological, phenotypical and cytogenetical criteria. In contrast, the subgroup of 51 patients with a CD20 bright profile is heterogeneous. Their significantly lower p27 expression level suggest the presence of a proliferative component, underlying a more aggressive disease. Further genomic studies are warranted to establish their precise nature. These cases should not be included in the same therapeutic trials as B-CLL.

Aged↗
PubMed2005

A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects.

Myeloproliferative disorders include several pathologies sharing the common feature of being clonal hematopoietic stem cell diseases. The molecular basis of chronic myeloid leukemia was characterized many years ago with the discovery of the t(9;22) translocation and its product the BCR-ABL oncoprotein. The recent finding of a recurrent mutation in the Janus 2 tyrosine kinase gene is a major advance in our understanding of the pathogenesis of several other myeloproliferative disorders, including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Although this work clearly identifies a frequent ( approximately 50%) subgroup of myeloproliferative disorders and explains most biological abnormalities described so far, it also raises the major question of how a single mutation can explain disease heterogeneity. Such a recurrent and unique mutation leading to a tyrosine kinase deregulation would make a suitable target for the development of specific therapies.

Gene Components↗
PubMed2005

A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.

Animals↗
PubMed2004

Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera.

Polycythemia vera (PV) is a myeloproliferative disorder arising in a multipotent hematopoietic stem cell. The pathogenesis of PV remains poorly understood; however, the biologic hallmark of this disease is the presence of erythropoietin (Epo)-independent colony formation (endogenous erythroid colony [EEC]) and cytokine hypersensitivity. We have developed a simple liquid culture from CD34+ cells to study PV erythroid differentiation. PV erythroid differentiation was characterized in this culture system by two types of abnormalities: 1) an increased proliferation of progenitors in response to cytokines, associated with strict cytokine dependency for preventing apoptosis; and 2) Epo-independent terminal erythroid differentiation in the presence of stem cell factor and interleukin-3 as evidenced by the acquisition of glycophorin A. The level of Epo-independent terminal differentiation correlates in PV patients with the number of EEC. Epo-independent terminal differentiation as well as normal Epo-induced differentiation were repressed by inhibitors of JAK2 (AG490), PI3K (LY294002), and the Src family kinases (PP2). In contrast, an inhibitor of the ERK/MAP kinase pathway (PD98059) had no effect on Epo-independent terminal differentiation. These signaling abnormalities were not mediated by a decreased expression or activity of the membrane tyrosine phosphatase CD45, which dephosphorylates JAK2 and Src family kinases. This study demonstrates that early steps of PV erythroid differentiation are strictly cytokine dependent. In contrast, late erythroid differentiation is an Epo-independent phenomenon that is mediated by signaling pathways identical to those in Epo-induced differentiation.

Antigens, CD34↗
PubMed2002

[New WHO classification of myelodysplastic syndromes. The consequences].

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders. Diagnosis and classification of MDS are based on morphological features of blood and bone marrow cells. The F.A.B. classification is widely used, but remains unclear in some cases of MDS. A World Health Organization (WHO) working group proposed a new classification of MDS, to improve the homogeneity of the different categories in term of physiopathology and prognosis. The new WHO classification incorporated some clinical and etiological data, and the results of cytogenetical or molecular analysis. The homologies and the differences between these two classification are showed, and the clinical consequences of the new classification are discussed.

Bone Marrow Cells↗
PubMed2002

[The place of growth factors in the treatment of myelodysplastic syndromes].

The myelodysplastic syndromes (MDS) are clonal hematological disorders characterized by ineffective hematopoiesis manifested by anemia, neutropenia, thrombocytopenia or a combination. Correction of these cytopenia is a priority in MDS without excess of blasts. Treatment of anemia depends mainly on erythrocyte transfusions. However with the ability of recombinant human hematopoietic growth factor many trials have been promoted. In vitro, erythroid progenitors from MDS patients are able to differentiate but they require much higher concentrations of erythropoietin than normal progenitors. Trials using rHu-Epo alone are disappointing. Combining rHu-Epo and rHu-G-CSF induces more encouraging results showing a synergistic effect particularly clear in sideroblastic anemia. Patients with low endogenous Epo level and low transfusion need are more likely to respond. Clinician should be able in the future to identify MDS patients with a chance of reversal of anemia or transfusion dependency.

Anemia↗
PubMed2002

[Update on malignant hemopathies].

The beginning of this century was marked, in our specialty as in other, by two revolutions: the routine use of molecular biology tools for a better prognosis of the disease (flt3 receptor duplication in AML, mutational profile of Ig genes in CLL, gene expression profile with ARN chips in aggressive lymphomas.), and the discovery of "intelligent" molecules, targeting the tumoral cell. In this category, the most appealing is the STI571 (Gleevec , Novartis), targeting the molecular abnormality of the cells expressing bcr-abl protein: CML, ALL Ph1(+). Other molecules targeting signal transduction proteins (ras farnesylation inhibitors for example) are already in clinical trials. The increasing therapeutic use of monoclonal antibodies is also to be cited, with a special mention concerning the rituximab, used in several B lymphoid pathologies, from lymphoma to autoimmune diseases. His very good tolerance permits his use in ambulatory patients, and his combination with chemotherapy or his linkage with radioactive elements render this molecule indispensable. The other side of these molecules is their incredibly high cost, explaining the uncontrolled expenses in 2001 of hospitals hosting hematology as well as oncology activities.

Acute Disease↗