Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes.

Mice deficient in the transcription factor Runx3 develop a multitude of immune system defects, including early onset colitis. This paper demonstrates that Runx3 is expressed in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2). Runx3 deletion in MNP causes early onset colitis due to their impaired maturation.

The Leo Sachs' legacy: a pioneer's journey through hematopoiesis.

Leo Sachs spent almost his entire scientific career in Israel, at the Weizmann Institute of Science, and became a worldwide renowned scientist for his pioneering studies in normal hematopoiesis, its breakdown in leukemia and the suppression of malignancy by inducing differentiation, thereby bypassing genetic defects that give rise to malignancy. The cell culture system he established in the early 1960s for the clonal development of normal hematopoietic cells, made it possible to discover the proteins that regulate the viability, proliferation and differentiation of different blood cell lineages, the molecular basis of normal hematopoiesis and the changes that drive leukemia. His studies established significant general concepts including: a) the value of a multi-gene cytokine network in regulating the viability, number and development of different cell types; b) the existence of alternative pathways that give flexibility to development in both normal and cancer cells; c) the response of some cancer cells to normal regulators of development; d) suppression of myeloid leukemia by inducing differentiation, bypassing malignancy-driving genetic defects; e) identification of chromosomes that control tumor suppression; f) discovering apoptosis as a major mechanism by which WT-p53 suppresses malignancy and g) the ability of hematopoietic cytokines to suppress apoptosis in both normal and leukemic cells.

Runx3 in Immunity, Inflammation and Cancer.

In this chapter we summarize the pros and cons of the notion that Runx3 is a major tumor suppressor gene (TSG). Inactivation of TSGs in normal cells provides a viability/growth advantage that contributes cell-autonomously to cancer. More than a decade ago it was suggested that RUNX3 is involved in gastric cancer development, a postulate extended later to other epithelial cancers portraying RUNX3 as a major TSG.

Runx3 at the interface of immunity, inflammation and cancer.

Inactivation of tumor suppressor genes (TSG) in normal cells provides a viability/growth advantage that contributes cell-autonomously to cancer. More than a decade ago claims arose that the RUNX3 member of the RUNX transcription factor family is a major TSG inactivated in gastric cancer, a postulate extended later to other cancers. However, evidence that Runx3 is not expressed in normal gastric and other epithelia has challenged the RUNX3-TSG paradigm.

Carcinogen-induced skin tumor development requires leukocytic expression of the transcription factor Runx3.

Carcinogen-induced skin tumorigenesis depends heavily on proinflammatory tumor-promoting processes. Here, we show that leukocytic Runx3 expression is central to the two-stage DMBA/TPA-induced skin tumorigenesis. Runx3-null mice were highly resistant to this process and concomitant ablation of Runx3 in dendritic and T cells fully recapitulated this resistance.

Transcription factor Runx3 regulates interleukin-15-dependent natural killer cell activation.

Natural killer cells belong to the family of innate lymphoid cells comprising the frontline defense against infected and transformed cells. Development and activation of natural killer cells is highly dependent on interleukin-15 signaling. However, very little is known about the transcription program driving this process.

Runx3-mediated transcriptional program in cytotoxic lymphocytes.

The transcription factor Runx3 is highly expressed in CD8(+) T and NK cytotoxic lymphocytes and is required for their effective activation and proliferation but molecular insights into the transcription program regulated by Runx3 in these cells are still missing. Using Runx3-ChIP-seq and transcriptome analysis of wild type vs. Runx3(-/-) primary cells we have now identified Runx3-regulated genes in the two cell types at both resting and IL-2-activated states.

Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1.

The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1-ETO (A-E) and CBFβ-SMMHC (C-S). The role of these oncoproteins in acute myeloid leukemia (AML) etiology has been well studied. Conversely, the function of native RUNX1 in promoting A-E- and C-S-mediated leukemias has remained elusive.

Cell-autonomous function of Runx1 transcriptionally regulates mouse megakaryocytic maturation.

RUNX1 transcription factor (TF) is a key regulator of megakaryocytic development and when mutated is associated with familial platelet disorder and predisposition to acute myeloid leukemia (FPD-AML). We used mice lacking Runx1 specifically in megakaryocytes (MK) to characterized Runx1-mediated transcriptional program during advanced stages of MK differentiation. Gene expression and chromatin-immunoprecipitation-sequencing (ChIP-seq) of Runx1 and p300 identified functional Runx1 bound MK enhancers.

Absence of Runx3 expression in normal gastrointestinal epithelium calls into question its tumour suppressor function.

The Runx3 transcription factor regulates cell fate decisions during embryonic development and in adults. It was previously reported that Runx3 is strongly expressed in embryonic and adult gastrointestinal tract (GIT) epithelium (Ep) and that its loss causes gastric cancer. More than 280 publications have based their research on these findings and concluded that Runx3 is indeed a tumour suppressor (TS).

Runx3 and T-box proteins cooperate to establish the transcriptional program of effector CTLs.

Activation of naive CD8(+) T cells with antigen induces their differentiation into effector cytolytic T lymphocytes (CTLs). CTLs lyse infected or aberrant target cells by exocytosis of lytic granules containing the pore-forming protein perforin and a family of proteases termed granzymes. We show that effector CTL differentiation occurs in two sequential phases in vitro, characterized by early induction of T-bet and late induction of Eomesodermin (Eomes), T-box transcription factors that regulate the early and late phases of interferon (IFN) gamma expression, respectively.

A regulatory interplay between miR-27a and Runx1 during megakaryopoiesis.

The transcription factor Runx1 is a key regulator of definitive hematopoiesis in the embryo and the adult. Lineage-specific expression of Runx1 involves transcription and post-transcription control through usage of alternative promoters and diverse 3'UTR isoforms, respectively. We identified and mapped microRNA (miR) binding sites on Runx1 3'UTR and show that miR-27a, miR-9, miR-18a, miR-30c, and miR-199a* bind and post-transcriptionally attenuate expression of Runx1.

Genes overexpressed in different human solid cancers exhibit different tissue-specific expression profiles.

We have analyzed gene expression in different normal human tissues and different types of solid cancers derived from these tissues. The cancers analyzed include brain (astrocytoma and glioblastoma), breast, colon, endometrium, kidney, liver, lung, ovary, prostate, skin, and thyroid cancers. Comparing gene expression in each normal tissue to 12 other normal tissues, we identified 4,917 tissue-selective genes that were selectively expressed in different normal tissues.

Developmentally regulated promoter-switch transcriptionally controls Runx1 function during embryonic hematopoiesis.

Background: Alternative promoters usage is an important paradigm in transcriptional control of mammalian gene expression. However, despite the growing interest in alternative promoters and their role in genome diversification, very little is known about how and on what occasions those promoters are differentially regulated. Runx1 transcription factor is a key regulator of early hematopoiesis and a frequent target of chromosomal translocations in acute leukemias.

Epigenetics and the plasticity of differentiation in normal and cancer stem cells.

Embryonic stem cells are characterized by their differentiation to all cell types during embryogenesis. In adult life, different tissues also have somatic stem cells, called adult stem cells, which in specific niches can undergo multipotent differentiation. The use of these adult stem cells has considerable therapeutic potential for the regeneration of damaged tissues.

Human cancers overexpress genes that are specific to a variety of normal human tissues.

We have analyzed gene expression data from three different kinds of samples: normal human tissues, human cancer cell lines, and leukemic cells from lymphoid and myeloid leukemia pediatric patients. We have searched for genes that are overexpressed in human cancer and also show specific patterns of tissue-dependent expression in normal tissues. Using the expression data of the normal tissues, we identified 4,346 genes with a high variability of expression and clustered these genes according to their relative expression level.

Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin.

NAD(P)H:quinone oxidoreductase 1 (NQO1) regulates the stability of the tumor suppressor WT p53. NQO1 binds and stabilizes WT p53, whereas NQO1 inhibitors including dicoumarol and various other coumarins and flavones induce ubiquitin-independent proteasomal p53 degradation and thus inhibit p53-induced apoptosis. Here, we show that curcumin, a natural phenolic compound found in the spice turmeric, induced ubiquitin-independent degradation of WT p53 and inhibited p53-induced apoptosis in normal thymocytes and myeloid leukemic cells.

Induction in myeloid leukemic cells of genes that are expressed in different normal tissues.

Using DNA microarray and cluster analysis of expressed genes in a cloned line (M1-t-p53) of myeloid leukemic cells, we have analyzed the expression of genes that are preferentially expressed in different normal tissues. Clustering of 547 highly expressed genes in these leukemic cells showed 38 genes preferentially expressed in normal hematopoietic tissues and 122 other genes preferentially expressed in different normal nonhematopoietic tissues, including neuronal tissues, muscle, liver, and testis. We have also analyzed the genes whose expression in the leukemic cells changed after activation of WT p53 and treatment with the cytokine IL-6 or the calcium mobilizer thapsigargin.

Runx3 regulates mouse TGF-beta-mediated dendritic cell function and its absence results in airway inflammation.

Runx3 transcription factor regulates cell lineage decisions in thymopoiesis and neurogenesis. Here we report that Runx3 knockout (KO) mice develop spontaneous eosinophilic lung inflammation associated with airway remodeling and mucus hypersecretion. Runx3 is specifically expressed in mature dendritic cells (DC) and mediates their response to TGF-beta.

Cytokines as suppressors of apoptosis.

Many cytokines have been isolated by their ability to induce growth and have been called growth factors. But these cytokines are also essential to induce cell viability, and cell viability and growth can be separately regulated. Using as examples myeloid hematopoietic cells, lymphocytes and neuronal cells, in vitro and in vivo studies have shown the role of cytokines in inducing viability of different cell types during development to mature cells.

P53 hot-spot mutants are resistant to ubiquitin-independent degradation by increased binding to NAD(P)H:quinone oxidoreductase 1.

Proteasomal degradation of p53 is mediated by two alternative pathways that are either dependent or independent of both Mdm2 and ubiquitin. The ubiquitin-independent pathway is regulated by NAD(P)H: quinone oxidoreductase 1 (NQO1) that stabilizes p53. The NQO1 inhibitor dicoumarol induces ubiquitin-independent p53 degradation.

Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis.

The RUNX transcription factors are important regulators of lineage-specific gene expression. RUNX are bifunctional, acting both as activators and repressors of tissue-specific target genes. Recently, we have demonstrated that Runx3 is a neurogenic transcription factor, which regulates development and survival of proprioceptive neurons in dorsal root ganglia.

Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes.

Using DNA microarray and clustering of expressed genes we have analyzed the mechanism of inhibition of wild-type p53-induced apoptosis by the cytokine interleukin 6 (IL-6) and the calcium mobilizer thapsigargin (TG). Clustering analysis of 1,786 genes, the expression level of which changed after activation of wild-type p53 in the absence or presence of IL-6 or TG, showed that these compounds did not cause a general inhibition of the ability of p53 to up-regulate or down-regulate gene expression. Expression of various p53 targets implicated as mediators of p53-induced apoptosis was also not affected by IL-6 or TG.