STAT5-and hypoxia-dependent upregulation of AXL

Internal tandem duplication in Fms-like tyrosine kinase 3 (FLT3-ITD) is the most frequent mutation observed in acute myeloid leukemia (AML) and correlates with poor prognosis. FLT3 tyrosine kinase inhibitors are promising for targeted therapy. Here, we investigated mechanisms dampening the response to the FLT3 inhibitor quizartinib, which is specific to the hematopoietic niche. Using AML primary samples and cell lines, we demonstrate that convergent signals from the hematopoietic microenvironment drive FLT3-ITD cell resistance to quizartinib through the expression and activation of the tyrosine kinase receptor AXL. Indeed, cytokines sustained phosphorylation of the transcription factor STAT5 in quizartinib-treated cells, which enhanced AXL expression by direct binding of a conserved motif in its genomic sequence. Likewise, hypoxia, another well-known hematopoietic niche hallmark, also enhanced AXL expression. Finally, in a xenograft mouse model, inhibition of AXL significantly increased the response of FLT3-ITD cells to quizartinib exclusively within a bone marrow environment. These data highlight a new bypass mechanism specific to the hematopoietic niche that hampers the response to quizartinib through combined upregulation of AXL activity. Targeting this signaling offers the prospect of a new therapy to eradicate resistant FLT3-ITD leukemic cells hidden within their specific microenvironment, thereby preventing relapses from FLT3-ITD clones

POLYDOM, UNE NOUVELLE PROTEINE COMPOSEE D'UNE ASSOCIATION UNIQUE DE DOMAINES EXTRACELLULAIRES

LE RENOUVELLEMENT PERMANENT DES CELLULES SANGUINES CIRCULANTES EST ASSURE PAR UN PETIT NOMBRE DE CELLULES SOUCHES HEMATOPOIETIQUES (CSH), LOCALISEES DANS LA MOELLE OSSEUSE CHEZ L'ADULTE. LE MICROENVIRONNEMENT MEDULLAIRE SYNTHETISE LA MAJORITE DES FACTEURS QUI REGULENT LES DIFFERENTES ETAPES DU DEVELOPPEMENT DES CSH EN CELLULES HEMATOPOIETIQUES MATURES ET FONCTIONNELLES. ACTUELLEMENT, DE NOMBREUX EFFECTEURS QUI PARTICIPENT AU DIALOGUE MOLECULAIRE ENTRE LES CELLULES STROMALES DU MICROENVIRONNEMENT MEDULLAIRE ET LES CSH, NE SONT PAS CONNUS. MON TRAVAIL DE THESE S'EST ORIENTE SUR L'IDENTIFICATION DE NOUVELLES MOLECULES PRODUITES PAR LA LIGNEE MS-5 QUI MIME IN VITRO LE STROMA MEDULLAIRE. NOUS AVONS UTILISE UNE APPROCHE DE RT-PCR ( REVERSE TRANSCRIPTASE-POLYMERASE CHAIN REACTION ) A PARTIR D'OLIGONUCLEOTIDES DEGENERES PERMETTANT D'IDENTIFIER DES GENES CONTENANT DES DOMAINES EGF-LIKE SEMBLABLES A CEUX DES GENES NOTCH. NOUS AVONS AINSI ISOLE UN NOUVEL ADN COMPLEMENTAIRE QUE NOUS AVONS ENTIEREMENT CLONE ET SEQUENCE. CET ADNC CODE POUR UNE PROTEINE EXTRACELLULAIRE DE 387 KILODALTON, QUE NOUS AVONS APPELEE POLYDOM. CETTE PROTEINE CONTIENT UN PEPTIDE SIGNAL SUIVI D'UN ENCHAINEMENT ORIGINAL DE HUIT MODULES DIFFERENTS QUI INCLUENT UN DOMAINE PENTRAXINE, UN DOMAINE VWF-A, DIX REPETITIONS EGF-LIKE, 34 MODULES CCP ET DEUX MODULES HYALINE REPEAT . L'ANALYSE DE CE DERNIER MODULE, NOUS A AMENE A DECRIRE UNE NOUVELLE FAMILLE DE MODULES PROTEIQUES EXTRACELLULAIRES QUI APPARTIENT A LA SUPERFAMILLE DE REPLIEMENT DE TYPE IMMUNOGLOBULINE. PARALLELEMENT A L'ETUDE STRUCTURALE DE POLYDOM, NOUS AVONS ANALYSE LE PROFIL D'EXPRESSION DU GENE CORRESPONDANT, NOTAMMENT AU SEIN DU TISSU HEMATOPOIETIQUE. L'ENSEMBLE DE NOS RESULTATS SUGGERENT QUE POLYDOM POURRAIT AVOIR UN ROLE BIOLOGIQUE IMPORTANT DANS L'ADHESION DES CELLULES STROMALES MEDULLAIRES OU/ET DANS LES REACTIONS IMMUNITAIRES INNEES.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Conversion myogénique striée de cellules humaines non musculaires

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Efficient in vitro myogenic reprogramming of human primary mesenchymal stem cells and endothelial cells by Myf5

International audienc

The HOXB4 Homeoprotein Differentially Promotes Ex Vivo Expansion of Early Human Lymphoid Progenitors

International audienc

Neuraminidase enhances in vitro expansion of human erythroid progenitors

International audienceIn spite of recent key improvements, in vitro mass production of erythrocytes from human stem cells is still limited by difficulties in obtaining sufficient numbers of erythroid progenitors. In fact, such progenitors are as scarce in the bone marrow as in peripheral blood. We used a two-step culture model of human cord blood-derived erythroid progenitors in the presence or absence of high-purity neuraminidase, in a serum-free, defined culture medium. Granulocytic and megakaryocytic progenitor cell expansions were also studied. We show that significant enhancement of erythroid cell generation is obtained when CD34(+) human hematopoietic progenitors are cultured in the presence of neuraminidase. Interestingly, in so doing, expanded red cell progenitors remained erythropoietin-dependent for further expansion and survival, and cells thus generated displayed a normal phenotype. Moreover, the activity of neuraminidase on these cells can be reversed by simple cell washing. Finally, growth of cells of the other myeloid lineages (granulocytes and megakaryocytes) is either decreased or unchanged in the presence of neuraminidase. This specific feature of neuraminidase, that of stimulation of human red cell progenitor proliferation, provides a safe technique for producing greater numbers of in vitro-generated red blood cells for both basic research and transfusion use

Structure and Transcription of the Human c-mpl Gene (MPL)

International audienc

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

International audienc