A role for RUNX1 in hematopoiesis and myeloid leukemia

Ichikawa, Motoshi; Yoshimi, Akihide; Nakagawa, Masahiro; Nishimoto, Nahoko; Watanabe‐Okochi, Naoko; Kurokawa, Mineo

doi:10.1007/s12185-013-1347-3

Cited by 96 publications

(85 citation statements)

References 80 publications

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“…In fact, our findings demonstrated that PITHD1 functioned to regulate megakaryocyte differentiation by modulating RUNX1 expression. RUNX1 deficiency due to point mutation or translocation is one of most important genetic events leading to leukemia [4]. PITHD1 seemed to upregulate endogenous RUNX1 and antagonize the effect of dominant negative form of RUNX1, which mimics the inhibitory effect of RUNX1 genetic alterations found in leukemia, on PMA-induced megakaryocyte differentiation.…”

Section: Pithd1 Promotes Megakaryocyte Differentiation In Mouse Fetalmentioning

confidence: 93%

“…Runt-related transcription factor 1 (RUNX1) plays an important role in normal hematopoiesis and its deficiency or dysfunction due to mutations and translocation is one of frequent genetic alterations in leukemia [4]. It is required for embryonic HSC but not for definitive HSC function.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, RUNX1 negatively regulates the proliferation of HSCs and myeloid progenitors [7,8]. In leukemia, the mutant RUXN1 or chimeric gene product repressed the function of remaining endogenous RUNX1 in hematopoiesis [4], suggesting that the expansion of hematopoietic stem and progenitor cells due to RUNX1-deficiency or dysfunction may be an important cause of human leukemias. Enhancing RUNX1 activity by upregulating the remaining endogenous RUNX1 expression may push leukemic cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

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Novel function of PITH domain-containing 1 as an activator of internal ribosomal entry site to enhance RUNX1 expression and promote megakaryocyte differentiation

Lü

Sun

Chen

et al. 2014

Cell. Mol. Life Sci.

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Introduction Altered gene expression coincides with leukemia development and may affect distinct features of leukemic cells. PITHD1 was significantly downregulated in leukemia and upregulated upon PMA induction in K562 cells undergoing megakaryocyte differentiation. We aimed to study the function of PITHD1 in megakaryocyte differentiation. Materials and methods K562 cells and fetal liver cells were used for either overexpression or downregulation of PITHD1 by retroviral or lentiviral transduction. FACS was used to detect the expression of CD41 and CD42 to measure megakaryocyte differentiation in these cells. Western blot and quantitative RT-PCR were used to measure gene expression. Dual luciferase assay was used to detect promoter or internal ribosomal entry site (IRES) activity. Results Ectopic expression of PITHD1 promoted megakaryocyte differentiation and increased RUNX1 expression while PITHD1 knockdown showed an opposite phenotype. Furthermore, PITHD1 efficiently induced endogenous RUNX1 expression and restored megakaryocyte differentiation suppressed by a dominant negative form of RUNX1. PITHD1 regulated RUNX1 expression at least through two distinct mechanisms: increasing transcription activity of proximal promoter and enhancing translation activity of an IRES element in exon 3. Finally, we confirmed the function of PITHD1 in regulating RUNX1 expression and megakaryopoiesis in mouse fetal liver cells. Conclusion and significance PITHD1 was a novel activator of IRES and enhanced RUNX1 expression that subsequently promoted megakaryocyte differentiation. Our findings shed light on understanding the mechanisms underlying megakaryopoiesis or leukemogenesis.

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Section: Pithd1 Promotes Megakaryocyte Differentiation In Mouse Fetalmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel function of PITH domain-containing 1 as an activator of internal ribosomal entry site to enhance RUNX1 expression and promote megakaryocyte differentiation

Lü

Sun

Chen

et al. 2014

Cell. Mol. Life Sci.

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“…In mammals, there are three RUNX genes: RUNX1, RUNX2 and RUNX3, each with distinct tissue specific expression patterns. RUNX1 is an extensively studied transcription factor which is well known in regulating development and maintenance of mammalian hematopoiesis and in translocation mediated leukemias' development (reviewed in [4]). Nevertheless, emerging functions of Runx1 in solid tumors have been recently shown.…”

Section: Saleh Khawaled and Rami I Aqeilanmentioning

confidence: 99%

Untitled

2017

Oncotarget

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News on: Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition by Hong et al. Oncotatget. 2017. doi: 10.18632/oncotarget.15381 Breast cancer is the most common cancer among women, and the second leading cause of deaths due to cancer in the US [1]. About 90% of deaths from cancer are due to metastasis, a complex process in which tumor cells escape the primary local tumor, invade through surrounding tissues to spread and colonize distant organs. Tumor cells frequently undergo epithelial-to-mesenchymal transition (EMT), a process whereby cells downregulate the epithelial specific adherens junction proteins including E-cadherin and re-express mesenchymal markers such as Vimentin and N-cadherin. As a result of this transition, the mesenchymal cells migrate from the epithelial layer and invade distant areas of the body [2]. Therefore, molecular characterization of EMT modulators could be a significant step toward better understanding and restraining of metastasis. In this issue, Hong and colleagues demonstrate a novel function of RUNX1 in sustaining mammary normal epithelial morphology and preventing EMT, and suggest that RUNX1 levels could be a prognostic indicator of breast cancer progression [3].RUNX transcription factors are essential regulators of diverse developmental processes, with roles in proliferation, differentiation, apoptosis and cell lineage specification. In mammals, there are three RUNX genes: RUNX1, RUNX2 and RUNX3, each with distinct tissue specific expression patterns. RUNX1 is an extensively studied transcription factor which is well known in regulating development and maintenance of mammalian hematopoiesis and in translocation mediated leukemias' development (reviewed in [4]). Nevertheless, emerging functions of Runx1 in solid tumors have been recently shown. Of particular interest, Runx1 is the predominant RUNX family member expressed in human breast epithelial cells [5]. The most compelling evidence for its role in breast cancer is the occurrence of RUNX1 somatic mutations in breast tumors [6].Furthermore, RUNX1 is one of the 17 genes whose expression pattern predicts breast cancer metastasis; its expression is less abundant in breast cancer as compared to normal breast epithelial cells, and it progressively decreases with increasing breast cancer aggression [7,8].In their latest study, Hong and coworkers identified a novel role of Runx1 in regulating breast cancer progression [3]. Initially, authors demonstrated that Runx1 NewsFigure 1: EMT activation inhibits Runx1-mediated mammary epithelial phenotype. A. In normal mammary conditions RUNX1 promotes transcription of epithelial markers, such as E-cadherin, and thus preserve a mammary epithelial cell phenotype. B.Activation of the EMT process either by TGF-β ligands or serum deprivation, leads to reduced Runx1 levels, by an unknown mechanism, and transcription of mesenchymal markers and hence inhibition of the epithelial markers, leading to epithelial-to-mesenchymal transition (EMT) and br...

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“…Ts65Dn mice, which are trisomic for 104 orthologs of Hsa21 genes, display persistent macrocytosis and develop a myeloproliferative disease characterized by megakaryocyte hyperplasia and dysplasia, and myelofibrosis [19]. Several genes on Hsa21, such as RUNX1, ETS2, ERG, GAPBA, BACH1, and DYRK1A, encode proteins relating to hematopoiesis and leukemogenesis [9,[21][22][23][24][25][26]. Further analysis of the models may reveal the effect of chromosome 21 gene dosage on human hematopoiesis and hematological malignancies.…”

Section: Abnormal Hematopoiesis In Dsmentioning

confidence: 99%

Evolution of myeloid leukemia in children with Down syndrome

Saida

2016

Int J Hematol

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the general population, the distribution of malignancies is different [3]. Patients with DS show a unique spectrum of malignancies, with a 10-to 20-fold higher risk of acute leukemia and a lower incidence of solid tumors [3,4]. Death from malignancies other than leukemia is strikingly less common in patients of all ages in DS, and death from leukemia is more likely in children younger than 10 years of age with DS than in those without [5]. The most frequent form of leukemia during childhood, both with and without DS, is acute lymphoblastic leukemia (ALL), and the incidence of ALL in children with DS is approximately 20-fold higher than in non-DS children [3]. However, the most marked increase in incidence in DS infants is with acute megakaryoblastic leukemia (AMKL), a myeloid malignancy of platelet precursors. The relative risk of developing AMKL is estimated to be 500 times higher in children with DS than in the general population [6]. Unlike AMKL in non-DS patients, most AMKL associated with DS (DS-AMKL) patients usually respond well to chemotherapy.In most cases, DS-AMKL is preceded by a temporary form of megakaryoblastic leukemia unique to newborns with DS and known as transient abnormal myelopoiesis (TAM) or transient leukemia. TAM, a clonal myeloproliferative syndrome, presents in the fetus or a few days after birth and in most cases resolves spontaneously within 3 months [7,8]. Typically, TAM is characterized by the presence of high numbers of circulating blast cells expressing CD33, CD38, CD117, CD34, CD7, CD56, CD36, CD71, and CD42b [9], which are indistinguishable from blasts observed in DS-AMKL. More often, the clinical presentation of TAM varies from asymptomatic alterations in the blood count to disseminated leukemic infiltration. Clinically severe TAM (liver failure, pleural/pericardial effusion, ascites, renal failure, and coagulopathy) affects 10-30 % of patients with clinically diagnosed TAM, and Abstract Children with Down syndrome (DS) have a markedly increased risk of leukemia. They are at particular risk of acute megakaryoblastic leukemia, known as myeloid leukemia associated with DS (ML-DS), the development of which is closely linked to a preceding temporary form of neonatal leukemia called transient abnormal myelopoiesis (TAM). Findings from recent clinical and laboratory studies suggest that constitutional trisomy 21 and GATA1 mutation(s) cause TAM, and that additional genetic alteration(s) including those in epigenetic regulators and signaling molecules are involved in the progression from TAM to ML-DS. Thus, this disease progression represents an important model of multi-step leukemogenesis. The present review focuses on the evolutionary process of TAM to ML-DS, and advances in the understanding of perturbed hematopoiesis in DS with respect to GATA1 mutation and recent findings, including cooperating genetic events, are discussed.

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A role for RUNX1 in hematopoiesis and myeloid leukemia

Cited by 96 publications

References 80 publications

Novel function of PITH domain-containing 1 as an activator of internal ribosomal entry site to enhance RUNX1 expression and promote megakaryocyte differentiation

Novel function of PITH domain-containing 1 as an activator of internal ribosomal entry site to enhance RUNX1 expression and promote megakaryocyte differentiation

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Evolution of myeloid leukemia in children with Down syndrome

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