title: AF1q/MLLT11 regulates the emergence of human prothymocytes through cooperative interaction with the Notch signaling pathway.
abstract: The mechanisms regulating the emergence of BM prothymocytes remain poorly characterized. Genome-wide transcriptome analyses looking for genes expressed in human prothymocytes led to the identification of AF1q/MLLT11 as a candidate gene conceivably involved in this process. Analysis of AF1q protein subcellular localization and intracellular trafficking showed that despite pronounced karyophily, it was subjected to constitutive nuclear export followed by ubiquitin-mediated degradation in the centrosomal area. Using in vitro assays based on either forced expression or shRNA-mediated silencing of AF1q, we provide evidence that the protein promotes T- over B-cell differentiation in multipotent hematopoietic progenitors. At the molecular level, AF1q confers to multipotent progenitors an increased susceptibility to Delta-like/Notch-mediated signaling. Consistent with these findings, enforced AF1q expression in humanized mice fosters the emergence of BM CD34(+)CD7(+) prothymocytes, enhances subsequent thymus colonization, and accelerates intrathymic T-cell development. In contrast, AF1q silencing provokes a global shift of BM lymphopoiesis toward the B-cell lineage, hinders prothymocyte development, inhibits thymus colonization, and leads to intrathymic accumulation of B cells. Our results indicate that AF1q cooperates with the Notch signaling pathway to foster the emergence of BM prothymocytes and drive subsequent intrathymic specification toward the T-cell lineage.
authors.affiliation: Laboratoire Développement du Système Immunitaire de l'Ecole Pratique des Hautes Etudes, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Parcelier
authors.forename: Nesrine
authors.initials: N
authors.lastname: Maharzi
authors.forename: Marc
authors.initials: M
authors.lastname: Delord
authors.forename: Macarena
authors.initials: M
authors.lastname: Robledo-Sarmiento
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Nelson
authors.forename: Halima
authors.initials: H
authors.lastname: Belakhdar-Mekid
authors.forename: Marika
authors.initials: M
authors.lastname: Pla
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kuranda
authors.forename: Veronique
authors.initials: V
authors.lastname: Parietti
authors.forename: Michele
authors.initials: M
authors.lastname: Goodhardt
authors.forename: Nicolas
authors.initials: N
authors.lastname: Legrand
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Gluckman
authors.forename: François
authors.initials: F
authors.lastname: Sigaux
authors.forename: Bruno
authors.initials: B
authors.lastname: Canque
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D020868:Gene Silencing; D006367:HeLa Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D038041:Lymphopoiesis; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism
chemical_list: C091736:MLLT11 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D046988:Proteasome Endopeptidase Complex