Msx2-interacting nuclear target protein (Mint) deficiency reveals negative regulation of early thymocyte differentiation by Notch/RBP-J signaling

Tsuji, Masazumi; Shinkura, Reiko; Kuroda, Kazuki; Yabe, Daisuke; Honjo, Tasuku

doi:10.1073/pnas.0610520104

Cited by 50 publications

(44 citation statements)

References 52 publications

(74 reference statements)

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“…This mode of repression adds to the classical concept of RBP-J-dependent repression, where RBP-J binds to target sequences in the absence of Notch signaling and recruits corepressors such as MINT/SHARP (34,40,50). Ligand signals are thought to displace these repressive complexes and allow the assembly of the RBP-J/NIC/Mastermind activator complex.…”

Section: Discussionmentioning

confidence: 99%

Ikaros Represses the Transcriptional Response to Notch Signaling in T-Cell Development

Kleinmann

Lay

Sellars

et al. 2008

Molecular and Cellular Biology

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Section: Discussionmentioning

confidence: 99%

Ikaros Represses the Transcriptional Response to Notch Signaling in T-Cell Development

Kleinmann

Lay

Sellars

et al. 2008

Molecular and Cellular Biology

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“…Unlike forced expression of AF1q or of Notch intracellular domain, SPEN deficiency does not affect B-cell development, but generates instead a thymic phenotype characterized by both enhanced generation of early thymic progenitors and subsequent intrathymic block at the DN2 stage. 35 The molecular mechanisms by which AF1q exerts its repressive effect on gene expression require further investigation. Even when tethered to a synthetic promoter, AF1q and A2M do not affect the transcriptional activity of a Luciferase reporter gene (A.P., unpublished data), indicating that AHDs do not correspond to docking sites for coactivators or corepressors.…”

Section: Discussionmentioning

confidence: 99%

AF1q/MLLT11 regulates the emergence of human prothymocytes through cooperative interaction with the Notch signaling pathway

Parcelier

Maharzi

Delord

et al. 2011

Blood

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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.

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“…OTT belongs to a family of proteins that interact with the transcription factor RBPJ (11)(12)(13)24), and constitutive activation of RBPJmediated transcription due to Notch signaling has been reported to result in increased self renewal and cancer (25,26). To better understand the mechanism of megakaryocytic transformation by OTT-MAL, we determined whether OTT-MAL could interfere with RBPJ-mediated transcriptional regulation.…”

Section: Conditional Expression Of Ott-mal In a Knockin Mouse Modelmentioning

confidence: 99%

The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model

Mercher¹,

Raffel²,

Moore³

et al. 2009

J. Clin. Invest.

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Acute megakaryoblastic leukemia (AMKL) is a form of acute myeloid leukemia (AML) associated with a poor prognosis. The genetics and pathophysiology of AMKL are not well understood. We generated a knockin mouse model of the one twenty-two-megakaryocytic acute leukemia (OTT-MAL) fusion oncogene that results from the t(1;22)(p13;q13) translocation specifically associated with a subtype of pediatric AMKL. We report here that OTT-MAL expression deregulated transcriptional activity of the canonical Notch signaling pathway transcription factor recombination signal binding protein for immunoglobulin κ J region (RBPJ) and caused abnormal fetal megakaryopoiesis. Furthermore, cooperation between OTT-MAL and an activating mutation of the thrombopoietin receptor myeloproliferative leukemia virus oncogene (MPL) efficiently induced a short-latency AMKL that recapitulated all the features of human AMKL, including megakaryoblast hyperproliferation and maturation block, thrombocytopenia, organomegaly, and extensive fibrosis. Our results establish that concomitant activation of RBPJ (Notch signaling) and MPL (cytokine signaling) transforms cells of the megakaryocytic lineage and suggest that specific targeting of these pathways could be of therapeutic value for human AMKL. IntroductionAcute megakaryoblastic leukemia (AMKL) is a heterogeneous subtype of acute myeloid leukemia (AML) and is more frequent in children than in adults (1-3). The molecular basis of AMKL is poorly understood in adults, whereas 2 major molecular subtypes are recognized in pediatric AMKL. The first group is represented by Down syndrome (DS) patients with both transient myeloproliferative disease (transient MPD) and AMKL who present with acquired GATA-binding protein 1 (GATA1) mutations, resulting in an N-terminal truncated GATA1 short (GATA1s) protein (4). The second group occurs in infants and is associated with the t(1;22)(p13;q13) chromosomal translocation, resulting in expression of the one twenty-two megakaryocytic acute leukemia (OTT-MAL) (also known as RBM15-MKL1) fusion protein (5-7).

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Msx2-interacting nuclear target protein (Mint) deficiency reveals negative regulation of early thymocyte differentiation by Notch/RBP-J signaling

Cited by 50 publications

References 52 publications

Ikaros Represses the Transcriptional Response to Notch Signaling in T-Cell Development

Ikaros Represses the Transcriptional Response to Notch Signaling in T-Cell Development

AF1q/MLLT11 regulates the emergence of human prothymocytes through cooperative interaction with the Notch signaling pathway

The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model

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