AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors

Nakagawa, Masahiro; Shimabe, Munetake; Watanabe‐Okochi, Naoko; Arai, Shunya; Yoshimi, Akihide; Shinohara, Akihito; Nishimoto, Nahoko; Kataoka, Keisuke; Sato, Tomohiko; Kumano, Keiki; Nannya, Yasuhito; Ichikawa, Motoshi; Imai, Yumiko; Kurokawa, Mineo

doi:10.1182/blood-2010-12-326710

Cited by 52 publications

(38 citation statements)

References 50 publications

(75 reference statements)

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“…Furthermore, the mechanism of this pathway's activation remains to be elucidated. Although several gene mutations found in hematologic malignancies have been reported to be associated with enhanced NF-κB signaling (20)(21)(22), these findings do not fully explain why the activation of NF-κB is observed in a number of different types of leukemia. It is more intriguing, as well as reasonable, to consider that NF-κB activation arises from the signaling pathways that are commonly involved in LICs.…”

Section: Introductionmentioning

confidence: 89%

Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

et al. 2014

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Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.

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Section: Introductionmentioning

confidence: 89%

Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

et al. 2014

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“…Phosphorylation of IkB by IkB kinase (IKK) degrades IkB, leading to nuclear import of NF-kB, which induces expression of NF-kB target genes. RUNX1 inhibits the enzymatic activity of IKK by binding to it in the cytoplasm, thereby suppressing the nuclear shuttling of NF-kB (Nakagawa et al 2011). …”

Section: Runx1 Post-translational Modifications In Transcriptional Rementioning

confidence: 98%

Covalent Modifications of RUNX Proteins: Structure Affects Function

Blumenthal

Greenblatt

Huang

et al. 2017

Advances in Experimental Medicine and Biology

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The RUNX family of transcription factors plays important roles in tissue-specific gene expression. Many of their functions depend on specific post-translational modifications (PTMs), and in this review, we describe how PTMs govern RUNX DNA binding, transcriptional activity, protein stability, cellular localization, and protein-protein interactions. We also report how these processes can be disrupted in disease settings. Finally, we describe how alterations of RUNX1, or the enzymes that catalyze its post-translational modifications, contribute to hematopoietic malignancies.

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“…85 The expansion of these immature cells observed in RUNX1-deficient mice could thus be relevant to the pathogenesis of human hematological tumors associated with a lack of RUNX1. 86 More recently, inactivating Runx1 during megakaryocytic maturation by crossing floxed mice with Pf4-cre mice has demonstrated the importance of this factor in Mouse models of constitutional thrombocytopenia haematologica | 2016; 101 (8)megakaryocyte maturation and allowed a genomic analysis of RUNX1-controlled gene expression during the late stages of megakaryocytopoiesis, again providing useful information for our understanding of FPD/AML. 87 …”

Section: Familial Platelet Disorder With a Predisposition For Acute Mmentioning

confidence: 99%

The contribution of mouse models to the understanding of constitutional thrombocytopenia

et al. 2016

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Article summary• Constitutional thrombocytopenias of hereditary origin have long been poorly studied due to the difficulties of obtaining invasive marrow samples.• Genetic engineering has allowed the generation of numerous mouse models for all these pathologies, providing invaluable information to understanding these diseases and serving as preclinical models to test new therapies.Constitutional thrombocytopenias result from genetic mutations affecting platelet production. These rare diseases are still underdiagnosed, especially in adults, because they remain little-known and have a highly variable expression. Autoimmune thrombocytopenia is still often wrongly diagnosed, thereby leading to the inadequate management of patients, with occasionally inappropriate splenectomy. The diagnosis of congenital thrombocytopenia relies on cytological and functional platelet analyses performed almost exclusively in specialized laboratories. Furthermore, about 50% of thrombocytopenias, associated or not with a thrombopathy, still remain of unknown origin. 1 In cases where platelet studies orient the diagnosis to a known disease, the detection of mutations in the suspected genes can C onstitutional thrombocytopenias result from platelet production abnormalities of hereditary origin. Long misdiagnosed and poorly studied, knowledge about these rare diseases has increased considerably over the last twenty years due to improved technology for the identification of mutations, as well as an improvement in obtaining megakaryocyte culture from patient hematopoietic stem cells. Simultaneously, the manipulation of mouse genes (transgenesis, total or conditional inactivation, introduction of point mutations, random chemical mutagenesis) have helped to generate disease models that have contributed greatly to deciphering patient clinical and laboratory features. Most of the thrombocytopenias for which the mutated genes have been identified now have a murine model counterpart. This review focuses on the contribution that these mouse models have brought to the understanding of hereditary thrombocytopenias with respect to what was known in humans. Animal models have either i) provided novel information on the molecular and cellular pathways that were missing from the patient studies; ii) improved our understanding of the mechanisms of thrombocytopoiesis; iii) been instrumental in structure-function studies of the mutated gene products; and iv) been an invaluable tool as preclinical models to test new drugs or develop gene therapies. At present, the genetic determinants of thrombocytopenia remain unknown in almost half of all cases. Currently available high-speed sequencing techniques will identify new candidate genes, which will in turn allow the generation of murine models to confirm and further study the abnormal phenotype. In a complementary manner, programs of random mutagenesis in mice should also identify new candidate genes involved in thrombocytopenia.The contribution of mouse models to the understanding of constitutional thrombocytope...

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AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors

Cited by 52 publications

References 50 publications

Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

Covalent Modifications of RUNX Proteins: Structure Affects Function

The contribution of mouse models to the understanding of constitutional thrombocytopenia

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