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3 results on '"Habbas K"'

1. AAV-delivery of diacylglycerol kinase kappa achieves long-term rescue of Fmr1-KO mouse model deficits of fragile X syndrome

Author

Hervé Moine, Françoise Piguet, Riet F, Cakil O, Ricardos Tabet, Doulaye Dembélé, Habbas K, Laufer R, Zambo B, Jean-Louis Mandel, Hocquemiller M, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, 0303 health sciences, Messenger RNA, [SDV]Life Sciences [q-bio], RNA-binding protein, Phosphatidic acid, Biology, medicine.disease, FMR1, Viral vector, Cell biology, Fragile X syndrome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, medicine, Signal transduction, 030217 neurology & neurosurgery, 030304 developmental biology, Diacylglycerol kinase
Abstract

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. It results from the lack of the RNA binding protein FMRP and is associated with the overactivation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk) is a main mRNA target of FMRP in cortical neurons. Here we show that diacylglycerol kinase kappa (DGKk), when modified as to become FMRP-independent and delivered into the brain of adolescent mice using adeno-associated viral vectors, corrects brain diacylglycerol and phosphatidic acid homeostasis and the main phenotypic behaviors of the Fmr1-KO mouse model of FXS. Thus, DGKk appears as a key triggering factor of FXS pathomechanism while providing a possible means of intervention for FXS gene therapy.One sentence summaryDGKk gene therapy in Fmr1-KO mouse model

Published
2021

2. AAV-delivered diacylglycerol kinase DGKk achieves long-term rescue of fragile X syndrome mouse model.

Author

Habbas K, Cakil O, Zámbó B, Tabet R, Riet F, Dembele D, Mandel JL, Hocquemiller M, Laufer R, Piguet F, and Moine H

Subjects
Animals, Diacylglycerol Kinase genetics, Diacylglycerol Kinase metabolism, Disease Models, Animal, Fragile X Mental Retardation Protein genetics, Fragile X Mental Retardation Protein metabolism, Mice, Mice, Knockout, Fragile X Syndrome genetics, Fragile X Syndrome metabolism, Fragile X Syndrome therapy
Abstract

Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1-KO mouse model. Here we show that adeno-associated viral vector delivery of a modified and FMRP-independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS-relevant behavioral phenotypes in the Fmr1-KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2022
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3. CDX2 expression in the hematopoietic lineage promotes leukemogenesis via TGFβ inhibition.

Author

Galland A, Gourain V, Habbas K, Güler Y, Martin E, Ebel C, Tavian M, Vallat L, Chenard MP, Mauvieux L, Freund JN, Duluc I, and Domon-Dell C

Subjects
Animals, CD11b Antigen genetics, Cell Lineage, Humans, Leukemia, Monocytic, Acute pathology, Membrane Proteins genetics, Mice, Signal Transduction, Tumor Microenvironment, CDX2 Transcription Factor genetics, Leukemia, Monocytic, Acute genetics, Transforming Growth Factor beta antagonists & inhibitors
Abstract

The intestine-specific caudal-related homeobox gene-2 (CDX2) homeobox gene, while being a tumor suppressor in the gut, is ectopically expressed in a large proportion of acute leukemia and is associated with poor prognosis. Here, we report that turning on human CDX2 expression in the hematopoietic lineage of mice induces acute monoblastic leukemia, characterized by the decrease in erythroid and lymphoid cells at the benefit of immature monocytic and granulocytic cells. One of the highly stimulated genes in leukemic bone marrow cells was BMP and activin membrane-bound inhibitor (Bambi), an inhibitor of transforming growth factor-β (TGF-β) signaling. The CDX2 protein was shown to bind to and activate the transcription of the human BAMBI promoter. Moreover, in a leukemic cell line established from CDX2-expressing mice, reducing the levels of CDX2 or Bambi stimulated the TGF-β-dependent expression of Cd11b, a marker of monocyte maturation. Taken together, this work demonstrates the strong oncogenic potential of the homeobox gene CDX2 in the hematopoietic lineage, in contrast with its physiological tumor suppressor activity exerted in the gut. It also reveals, through BAMBI and TGF-β signaling, the involvement of CDX2 in the perturbation of the interactions between leukemia cells and their microenvironment., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Published
2021
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