CDX2 expression in the hematopoietic lineage promotes leukemogenesis via TGFβ inhibition

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

Diacylglycerol kinase kappa (DGKκ) as a new therapeutic target in the Fmr1-KO mouse model of fragile X syndrome

Le syndrome de l’X fragile (FXS) est la première cause familiale de déficience intellectuelle et d'autisme. Le FXS est causé par l'absence de la protéine FMRP causée par l’inactivation du gène FMR1. Comprendre comment l'absence de FMRP conduit à des altérations synaptiques est important pour définir les bases moléculaires du FXS et identifier un traitement. Dans les neurones corticaux, FMRP contrôle la traduction de la diacylglycérol kinase DgkK, une enzyme contrôlant la signalisation lipidique et dont la dérégulation est suffisante pour récapituler les phénotypes de type FXS. Sur la base de ces données suggérant que la DgkK joue un rôle clé dans le mécanisme pathologique du FXS, nous avons ciblé l'activité de la DGK par des approches pharmaceutiques et de thérapie génique. Chez la souris Fmr1-KO, un agoniste des DGK, la pioglitazone, corrige la signalisation excessive du DAG et les comportements FXS. Les virus adéno-associés (AAV) exprimant un transgène FMRP indépendant de la DgkK corrigent également les phénotypes FXS. Dans l'ensemble, nos données indiquent que la dérégulation de la DgkK contribue au FXS et représente une cible thérapeutique prometteuse.The Fragile X syndrome (FXS) is the first familial cause of intellectual disability and autism. FXS is caused by the absence of the FMRP protein caused by FMR1 gene silencing. Understanding how the lack of FMRP leads to synaptic alterations is important to define the molecular basis of FXS and identify a treatment. In cortical neurons, FMRP controls the translation of diacylglycerol kinase DgkK, a master regulator controlling lipid signaling and whose deregulation is sufficient to recapitulate FXS-like phenotypes. Based on these data suggesting that DgkK plays a key role in FXS pathomechanism, we targeted DGK activity by pharmaceutical and gene-therapy approaches. In Fmr1-KO mouse, DGK agonist pioglitazone corrects excessive DAG signaling and FXS behaviors. Adeno-associated viruses (AAV) expressing an FMRP-independent-DgkK transgene also rescue FXS phenotypes. Altogether our data indicate that DgkK deregulation contributes to FXS and represents a promising therapeutic target

La diacyglycérol kinase kappa (Dgkκ) comme nouvelle cible thérapeutique dans le modèle murin Fmrl-KO du syndrome de l'X fragile

The Fragile X syndrome (FXS) is the first familial cause of intellectual disability and autism. FXS is caused by the absence of the FMRP protein caused by FMR1 gene silencing. Understanding how the lack of FMRP leads to synaptic alterations is important to define the molecular basis of FXS and identify a treatment. In cortical neurons, FMRP controls the translation of diacylglycerol kinase DgkK, a master regulator controlling lipid signaling and whose deregulation is sufficient to recapitulate FXS-like phenotypes. Based on these data suggesting that DgkK plays a key role in FXS pathomechanism, we targeted DGK activity by pharmaceutical and gene-therapy approaches. In Fmr1-KO mouse, DGK agonist pioglitazone corrects excessive DAG signaling and FXS behaviors. Adeno-associated viruses (AAV) expressing an FMRP-independent-DgkK transgene also rescue FXS phenotypes. Altogether our data indicate that DgkK deregulation contributes to FXS and represents a promising therapeutic target.Le syndrome de l’X fragile (FXS) est la première cause familiale de déficience intellectuelle et d'autisme. Le FXS est causé par l'absence de la protéine FMRP causée par l’inactivation du gène FMR1. Comprendre comment l'absence de FMRP conduit à des altérations synaptiques est important pour définir les bases moléculaires du FXS et identifier un traitement. Dans les neurones corticaux, FMRP contrôle la traduction de la diacylglycérol kinase DgkK, une enzyme contrôlant la signalisation lipidique et dont la dérégulation est suffisante pour récapituler les phénotypes de type FXS. Sur la base de ces données suggérant que la DgkK joue un rôle clé dans le mécanisme pathologique du FXS, nous avons ciblé l'activité de la DGK par des approches pharmaceutiques et de thérapie génique. Chez la souris Fmr1-KO, un agoniste des DGK, la pioglitazone, corrige la signalisation excessive du DAG et les comportements FXS. Les virus adéno-associés (AAV) exprimant un transgène FMRP indépendant de la DgkK corrigent également les phénotypes FXS. Dans l'ensemble, nos données indiquent que la dérégulation de la DgkK contribue au FXS et représente une cible thérapeutique prometteuse

Diacylglycerol kinase kappa (DGKκ) as a new therapeutic target in the Fmr1-KO mouse model of fragile X syndrome

Le syndrome de l’X fragile (FXS) est la première cause familiale de déficience intellectuelle et d'autisme. Le FXS est causé par l'absence de la protéine FMRP causée par l’inactivation du gène FMR1. Comprendre comment l'absence de FMRP conduit à des altérations synaptiques est important pour définir les bases moléculaires du FXS et identifier un traitement. Dans les neurones corticaux, FMRP contrôle la traduction de la diacylglycérol kinase DgkK, une enzyme contrôlant la signalisation lipidique et dont la dérégulation est suffisante pour récapituler les phénotypes de type FXS. Sur la base de ces données suggérant que la DgkK joue un rôle clé dans le mécanisme pathologique du FXS, nous avons ciblé l'activité de la DGK par des approches pharmaceutiques et de thérapie génique. Chez la souris Fmr1-KO, un agoniste des DGK, la pioglitazone, corrige la signalisation excessive du DAG et les comportements FXS. Les virus adéno-associés (AAV) exprimant un transgène FMRP indépendant de la DgkK corrigent également les phénotypes FXS. Dans l'ensemble, nos données indiquent que la dérégulation de la DgkK contribue au FXS et représente une cible thérapeutique prometteuse.The Fragile X syndrome (FXS) is the first familial cause of intellectual disability and autism. FXS is caused by the absence of the FMRP protein caused by FMR1 gene silencing. Understanding how the lack of FMRP leads to synaptic alterations is important to define the molecular basis of FXS and identify a treatment. In cortical neurons, FMRP controls the translation of diacylglycerol kinase DgkK, a master regulator controlling lipid signaling and whose deregulation is sufficient to recapitulate FXS-like phenotypes. Based on these data suggesting that DgkK plays a key role in FXS pathomechanism, we targeted DGK activity by pharmaceutical and gene-therapy approaches. In Fmr1-KO mouse, DGK agonist pioglitazone corrects excessive DAG signaling and FXS behaviors. Adeno-associated viruses (AAV) expressing an FMRP-independent-DgkK transgene also rescue FXS phenotypes. Altogether our data indicate that DgkK deregulation contributes to FXS and represents a promising therapeutic target

Feature selection based bee swarm meta-heuristic approach for combinatorial optimisation problems: a case-study on MaxSAT

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AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model

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

CDX2

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

CDX2 expression in the hematopoietic lineage promotes leukemogenesis via TGFβ inhibition

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