TLX1/HOX11-Mediated Disruption of Hematopoietic Differentiation Programs.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2997-2997
Author(s):  
Irene Riz ◽  
Sergey S. Akimov ◽  
Shannon S. Eaker ◽  
Leonardo Marino-Ramirez ◽  
David Landsman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cell Line ◽  
Expression Profiles ◽  
Erythroid Differentiation ◽  
Embryoid Bodies ◽  
Model Systems ◽  
Transcriptional Networks ◽  
Hematopoietic Differentiation

Abstract The diverged TLX1/HOX11 homeobox gene is frequently transcriptionally activated in T-cell acute lymphoblastic leukemia as a result of two recurrent chromosomal translocations or by as yet unknown mechanisms. Sporadic expression of TLX1 has also been detected in some other human tumors, raising the possibility that TLX1 played a role in the etiology of these malignancies. In this context, it is noteworthy that TLX1 is aberrantly expressed in the human erythroleukemia cell line K562. We previously reported that enforced TLX1 expression immortalizes myeloid progenitors in murine bone marrow and erythroid progenitors originating from murine embryonic stem cell-derived embryoid bodies. Based on these findings, we speculated that dysregulated TLX1 expression contributes to neoplastic transformation by interfering with hematopoietic differentiation programs. Here we carried out genome-wide expression profiling on these model systems to elucidate the mechanism of TLX1-mediated differentiation arrest. Surprisingly, these investigations uncovered a latent erythroid phenotype of the TLX1+ bone marrow progenitor cell lines. Transcriptome comparison with murine GATA-1-null G1E-ER4 erythroblast cells (GEO Accession No. GDS568) showed nonrandom overlap (P = 2.3 × 10−5) with a set of genes that immediately respond to GATA-1 activation. Included among the genes for which a positive correlation was observed were the erythropoietin (Epo) receptor and several functionally-associated downstream signaling components such as Lyn and Dok-1, as well as the SCL and FOG-1 transcription factor genes. We confirmed the biological relevance of these findings by demonstrating that TLX1-immortalized bone marrow progenitors proliferated in response to erythropoietin, synthesizing beta-globin mRNA. We next extended this approach to iEBHX1S-4 cells, an embryoid body-derived cell line generated by conditional (doxycycline-controlled) TLX1 expression (manuscript in preparation). iEBHX1S-4 cells require IL-3 plus stem cell factor for survival and proliferation. However, when doxycycline is removed from the culture medium, the cells undergo Epo-dependent erythroid differentiation characterized by up-regulation of the TER119 surface antigen and hemoglobin synthesis. Interestingly, whereas there was statistically significant overlap of gene expression profiles between constitutive and conditional TLX1+ cells (P = 2.5 × 10−5), there were no significant similarities between the iEBHX1S-4 transcriptome and the G1E-ER4 dataset until 6–24 hours after release of the TLX1 differentiation block. Bioinformatics analysis of the upstream regulatory regions of the genes identified implicated transcriptional networks involving GATA-1 as well as the p53, NF-kappaB and Egr-1 transcription factors. All of these transcription factors are substrates of the acetyltransferase CREB-binding protein (CBP), suggesting that inappropriate TLX1 expression might interfere with CBP activity. In agreement with this notion, acetylation of GATA-1, a key substrate of CBP-modulated erythroid differentiation, was increased upon down-regulation of TLX1 expression in iEBHX1S-4 cells. Experiments to directly confirm TLX1 inhibition of CBP as a central facet of TLX1 transforming function are ongoing, the results of which will be presented.

scholarly journals Genes Involved in the Transcriptional Regulation of Pluripotency Are Expressed in Malignant Tumors of the Uterine Cervix and Can Induce Tumorigenic Capacity in a Nontumorigenic Cell Line

2019 ◽  
Vol 2019 ◽  
pp. 1-14
Author(s):  
Graciela Ruiz ◽  
Heriberto A. Valencia-González ◽  
Delia Pérez-Montiel ◽  
Felipe Muñoz ◽  
Rodolfo Ocadiz-Delgado ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Stem Cell ◽  
Transcription Factors ◽  
Cancer Stem Cell ◽  
Cell Line ◽  
Target Genes ◽  
Malignant Tumors ◽  
Expression Profiles ◽  
Ectopic Expression ◽  
Normal Tissues

Transcription factors OCT4, SOX2, KLF4, C-MYC, and NANOG (OSKM-N) regulate pluripotency and stemness, and their ectopic expression reprograms human and murine fibroblasts that constitute the key of regenerative medicine. To determine their contribution to cell transformation, we analyzed the gene expression profiles of these transcription factors in cervical cancer samples and found that they are preferentially expressed in the tumor component. Also, cancer stem cell-enriched cultures grown as sphere cultures showed overexpression of OSKM-N genes. Importantly, we observed that lentiviral-mediated transduction of these factors confers, to a nontumorigenic immortalized human cell line, properties of cancer stem cells as the ability to form tumors in a mouse model. When we performed a meta-analysis using microarray data from cervical cancer biopsies and normal tissues, we found that the expression of OSKM-N and some target genes allowed separating tumor and normal tissues between samples, which enhanced the importance of OSKM-N in the tumorigenesis. Finally, we analyzed and compared both transcript and protein expression profiles of these factors within a cohort of patients with cervical cancer. To our knowledge, this is the first time that the expression of OSKM-N is described to induce one of the main characteristics of the cancer stem cell, the tumorigenicity. And, more importantly, its exogenous expression in a nontumorigenic cell line is sufficient to induce a tumorigenic phenotype; furthermore, the differential expression of this transcription factor distinguishes tumor tissue and normal tissue in cervical samples.

SON Regulates GATA-2 Through Transcriptional Control of the Mir-23a∼27a∼24-2 Cluster

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 110-110
Author(s):  
Eun-Young Ahn ◽  
Tsunehito Higashi ◽  
Ming Yan ◽  
Shinobu Matsuura ◽  
Miao-Chia Lo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
Cell Line ◽  
Protein Level ◽  
Bone Marrow Cells ◽  
Mrna Level ◽  
Luciferase Reporter ◽  
Hematopoietic Differentiation ◽  
Reporter Construct ◽  
Marrow Cells

Abstract Abstract 110 While characterizing AML1-ETO domains important for leukemia development and identifying proteins interacting with these domains, we discovered SON as a novel AML1-ETO binding protein (PNAS, 2008, 105:17103). SON is a large, poorly characterized serine/arginine rich SR protein localized to nuclear speckles. SON has DNA, single stranded RNA, and double stranded RNA binding domains and long repeats of amino acids. Overexpression of a partial fragment of SON in a transformed cell line decreased the tumorigenic potential of the cell in nude mice and protected yeast from apoptosis. However, partially due to its large size, the SON protein has not been well characterized. Recently, we reported that SON plays an important role in RNA splicing of a specific set of cell cycle related genes: ones that possess weak splice sites (Molecular Cell, 2011, 42:185). While SON is expressed ubiquitously, its expression level is noticeably higher in hematopoietic organs/tissues and blood cells compared to other tissues, suggesting important roles of SON in the hematopoietic system. To examine whether SON expression is regulated during hematopoietic differentiation, we measured relative mRNA level of mouse Son in different stages of hematopoiesis. Son mRNA level is higher in lineage marker negative (Lin-) bone marrow cells when compared to total bone marrow cells. Macrophages showed less expression of Son, suggesting that Son is down-regulated along the hematopoietic differentiation. We further sorted Lin- cells and measured the Son level in LSK (Lin-, Sca1+, cKit+), CMP (commom myeloid progenitors), GMP (granulocyte/monocyte progenitors) and MEP (megakaryocyte/erythroid progenitors) populations. LSK cells, which precede other progenitors, showed the highest level of Son. In addition, we confirmed that SON is down-regulated during TPA-induced monocytic differentiation of U937 myeloid cells. Taken together, SON is more abundantly expressed in immature hematopoietic cells and down-regulated during differentiation. Since SON is differentially expressed during hematopoietic differentiation, we examined whether SON is involved in regulation of hematopoietic transcription factors that are key dictators of hematopoietic differentiation. Among the several transcription factors analyzed, we found that Gata-2 mRNA was consistently reduced by two different Son shRNAs in Lin- bone marrow cells. Down regulation of the GATA-2 mRNA level was further confirmed in human K562 leukemic cell line. More interestingly, while having 20∼40% reduction of mRNA level, the GATA-2 protein level is more remarkably down-regulated upon SON knockdown, resulting in 75∼90% reduction. These results indicate that upon SON knockdown, GATA-2 protein level is mainly regulated at the post-transcriptional steps. Sequence analysis of the 3' UTR of the human GATA-2 gene predicted several candidates of targeting microRNAs. Among them, we confirmed that the mature form of miR-27a and miR-24 are up-regulated upon SON knockdown. Next, we tested the effect of over-expression of miR-27a and miR-24 on GATA-2 expression using a GATA-2 3' UTR-containing luciferase reporter construct and demonstrated that miR-27a indeed inhibits GATA-2 mRNA level. miR-27a is a member of the miR-23a∼27a∼24-2 cluster. RTqPCR showed that primary miRNA of the miR-23a∼27a∼24 cluster is upregulated upon SON knockdown. To test whether the increase of pri-miR of this cluster is due to promoter activation, we used a reporter construct containing the promoter sequence of the miR-23a∼27a∼24-2 cluster fused to the luciferase reporter. The expression of luciferase driven by this promoter is significantly elevated upon SON knockdown, suggesting that that SON functions to repress transcription of the miR-23a-27a-24-2 cluster, thereby relieving GATA-2 mRNA from targeting by miR-27a, and contributes to maintaining the GATA-2 protein level. Taken together, our results reveal a previously unidentified function of SON in microRNA transcription and controlling the GATA-2 protein level in hematopoietic cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Closer to Nature: The Role of MSCs in Recreating the Microenvironment of the Hematopoietic Stem Cell Niche in vitro

2022 ◽  
pp. 1-10
Author(s):  
Patrick Wuchter ◽  
Anke Diehlmann ◽  
Harald Klüter
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Model Systems ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Niche ◽  
Cell Niche

<b><i>Background:</i></b> The stem cell niche in human bone marrow provides scaffolds, cellular frameworks and essential soluble cues to support the stemness of hematopoietic stem and progenitor cells (HSPCs). To decipher this complex structure and the corresponding cellular interactions, a number of in vitro model systems have been developed. The cellular microenvironment is of key importance, and mesenchymal stromal cells (MSCs) represent one of the major cellular determinants of the niche. Regulation of the self-renewal and differentiation of HSPCs requires not only direct cellular contact and adhesion molecules, but also various cytokines and chemokines. The C-X-C chemokine receptor type 4/stromal cell-derived factor 1 axis plays a pivotal role in stem cell mobilization and homing. As we have learned in recent years, to realistically simulate the physiological in vivo situation, advanced model systems should be based on niche cells arranged in a three-dimensional (3D) structure. By providing a dynamic rather than static setup, microbioreactor systems offer a number of advantages. In addition, the role of low oxygen tension in the niche microenvironment and its impact on hematopoietic stem cells need to be taken into account and are discussed in this review. <b><i>Summary:</i></b> This review focuses on the role of MSCs as a part of the bone marrow niche, the interplay between MSCs and HSPCs and the most important regulatory factors that need to be considered when engineering artificial hematopoietic stem cell niche systems. <b><i>Conclusion:</i></b> Advanced 3D model systems using MSCs as niche cells and applying microbioreactor-based technology are capable of simulating the natural properties of the bone marrow niche more closely than ever before.

scholarly journals Suppression of Carbon Tetrachloride-Induced Liver Fibrosis by Transplantation of a Clonal Mesenchymal Stem Cell Line Derived from Rat Bone Marrow

2009 ◽  
Vol 18 (1) ◽  
pp. 89-100 ◽  
Author(s):  
Marhaen Hardjo ◽  
Masahiro Miyazaki ◽  
Masakiyo Sakaguchi ◽  
Takuro Masaka ◽  
Sukaeni Ibrahim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Mesenchymal Stem Cell ◽  
Cell Line ◽  
Stem Cell Line ◽  
Rat Bone

scholarly journals Stem cell factor influences the proliferation and erythroid differentiation of the MB-02 human erythroleukemia cell line by binding to a high-affinity c-kit receptor

Blood ◽  
1993 ◽  
Vol 82 (2) ◽  
pp. 436-444 ◽  
Author(s):  
VC Broudy ◽  
DA Morgan ◽  
N Lin ◽  
KM Zsebo ◽  
FW Jacobsen ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Stem Cell ◽  
Growth Factors ◽  
Cell Line ◽  
Stem Cell Factor ◽  
Erythroid Differentiation ◽  
Gm Csf ◽  
High Affinity ◽  
Kit Receptor ◽  
Erythroleukemia Cell

Abstract Stem cell factor (SCF) acts in synergy with other growth factors such as erythropoietin (Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF), or interleukin-3 (IL-3), to stimulate the growth of primitive hematopoietic cells. Because of the prominent role of CSF in the maintenance of normal erythropoiesis in vivo, we examined the effects of SCF on the Epo-inducible human erythroleukemia cell line MB- 02, and characterized the c-kit receptor in these cells. MB-02 cells cultured in serum-containing media do not survive in the absence of exogenous growth factors, but the addition of SCF, Epo, or IL-3 as a single factor enhanced MB-02 survival. Furthermore, in the presence of Epo, SCF (5 to 25 ng/mL) enhanced MB-02 proliferation in a dose- dependent manner, and increased the relative and absolute number of benzidine-positive cells generated. SCF also enhanced cell proliferation in the presence of either IL-3 or low concentrations of GM-CSF. A neutralizing anti-c-kit receptor monoclonal antibody (SR-1) blocked binding of 125I-SCF to MB-02 cells by 98%, and the effect of SCF on MB-02 growth, c-kit receptor-binding parameters were quantitated by equilibrium-binding experiments with 125I-SCF. MB-02 cells display a single class of high-affinity (50 pmol/L) c-kit receptors, with approximately 8,000 receptors per cell. The molecular weight of the c- kit receptor was determined by affinity cross-linking 125I-SCF to MB-02 cells. 125I-SCF-c-kit receptor complexes of approximately 155,000 and approximately 310,000 daltons were found, likely representing the monomeric and dimeric forms of the c-kit receptor. The binding affinity and molecular weight of the c-kit receptor on MB-02 cells are similar to those of normal human marrow cells. These results suggest that SCF synergizes with Epo to influence not only the proliferation but the erythroid differentiation of MB-02 cells. Thus, the MB-02 cell line may be a useful model in which to investigate the molecular mechanisms of SCF action.

scholarly journals In Vitro Murine Hematopoiesis Supported by Signaling from a Splenic Stromal Cell Line

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Hong Kiat Lim ◽  
Pravin Periasamy ◽  
Helen C. O’Neill
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Stromal Cell ◽  
Hematopoietic Cells ◽  
Model Systems ◽  
Hematopoietic Stem ◽  
Cell Production ◽  
Stromal Cell Line ◽  
Reticular Cells

There are very few model systems which demonstrate hematopoiesis in vitro. Previously, we described unique splenic stromal cell lines which support the in vitro development of hematopoietic cells and particularly myeloid cells. Here, the 5G3 spleen stromal cell line has been investigated for capacity to support the differentiation of hematopoietic cells from progenitors in vitro. Initially, 5G3 was shown to express markers of mesenchymal but not endothelial or hematopoietic cells and to resemble perivascular reticular cells in the bone marrow through gene expression. In particular, 5G3 resembles CXCL12-abundant reticular cells or perivascular reticular cells, which are important niche elements for hematopoiesis in the bone marrow. To analyse the hematopoietic support function of 5G3, specific signaling pathway inhibitors were tested for the ability to regulate cell production in vitro in cocultures of stroma overlaid with bone marrow-derived hematopoietic stem/progenitor cells. These studies identified an important role for Wnt and Notch pathways as well as tyrosine kinase receptors like c-KIT and PDGFR. Cell production in stromal cocultures constitutes hematopoiesis, since signaling pathways provided by splenic stroma reflect those which support hematopoiesis in the bone marrow.

Microrna Expression Profiling in Acute Myelogenous Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1131-1131
Author(s):  
Fernando J. Suarez Saiz ◽  
Serban San-Marina ◽  
Mark D. Minden
Keyword(s):  
Bone Marrow ◽  
Cell Line ◽  
Cell Lines ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Erythroid Cell ◽  
Normal Bone Marrow ◽  
Hematopoietic Differentiation ◽  
Normal Bone ◽  
Acute Myelogenous

Abstract Acute myelogenous leukemia (AML) arises due to changes in gene expression that block or alter the normal differentiation program of hematopoietic stem cells. A variety of mutations in protein-encoding genes have been shown to contribute to the development of leukemia. Recently a new class of genes called microRNAs (miRNAs) have been identified. miRNAs are a subgroup of highly conserved, non-coding RNAs found only in eukaryotes. They do not encode proteins, and appear to have a significant effect on the proteome of a cell. Their conservation between species suggests their involvement in important biological functions, and in fact been shown to be involved in hematopoietic differentiation. While the function of most miRNAs is still unknown, it is believed that they regulate expression of target mRNAs by using the siRNA machinery either to promote degradation of the mRNA or to block its translation. To begin to understand the role of miRNAs in AML, we used Quantitative Polymerase Chain Reaction (QPCR) to measure the expression level of 20 miRNA precursors in the pro erythroid cell line K562, the pro-myelocytic cell line NB4, the myelomococytic cell line OCI/AML2, AML patients’ blasts and in normal bone marrow (NBM). The investigated miRNAs included some that are known to be specific for hematopoietic tissues or involved in hematopoietic differentiation, as well as all the miRNAs in chromosome 7, a hot spot for gene deletion in AML. Our findings indicate that miRNAs are differentially expressed in patients and cell lines when compared among themselves and against normal bone marrow. For example pre-miR-142 was expressed in NBM and K562 but was found to be elevated in OCI/AML2, NB4 and in all patient samples. Pre-miR-20 was found to be overexpressed in only a subset of patients. Other miRNAs like pre-miR-335 and pre-miR-148a were expressed in NBM and in some patients and not in the cell lines. In an effort to identify possible regulators of miRNA expression, we analyzed the upstream region of pre-miR-142 and found an LMO2 binding site. In AML, the LMO2 gene can be overexpressed relative to normal bone marrow and healthy lymphocytes. This transcription factor is involved in the regulation of genes important in the development of blood cells. To investigate if LMO2 could be involved in the regulation of miR-142 expression, we performed chromatin immunoprecipitation (ChIP) from K562 using an anti-LMO2 antibody. Only the LMO2 immunoprecipitation, and not those from the pre-immune control, were enriched in promoter DNA for pre-miR-142. This is consistent with the observation that miRNAs and coding RNAs can be regulated by the same environmental signals. Based on this observation we propose that oncogenes regulate in part the phenotype and biological behaviour of leukemia by affecting the expression of miRNAs. This further suggests that different forms of leukemia may be recognized based upon the spectrum of miRNAs they express.

Erythroid Transcription Factor GATA-1 Binds and Represses PU.1 Gene – Candidate Mechanism Of Epigenetic Repression Of PU.1 and Inefficient Erythropoiesis In MDS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1558-1558
Author(s):  
Pavel Burda ◽  
Nikola Curik ◽  
Nina Dusilkova ◽  
Giorgio L Papadopoulos ◽  
John Strouboulis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transcription Factors ◽  
High Risk ◽  
Cell Growth ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Chromatin Structure ◽  
Binding Sites ◽  
Erythroid Differentiation ◽  
Ineffective Erythropoiesis

Abstract Introduction Myelodysplastic syndrome (MDS) is often manifested by anemia due to ineffective erythropoiesis. Upon transformation to MDS/AML the uniform population of leukemic blasts overgrow dysplastic bone marrow. Hematopoiesis is regulated by transcription factors GATA-1 and PU.1 that interact and mutually inhibit each other in progenitor cells to guide multilineage commitment and subsequent lineage differentiation. Expression of PU.1 is controlled by several transcription factors including PU.1 itself at distal URE enhancer. It has been well established that underexpression of PU.1 in progenitor cells leads to AML (Rosenbauer F et al. 2004). In addition, co-expression of PU.1 and GATA-1 in AML-erythroleukemia (EL) blasts prevents induction of differentiation programs regulated by these transcription factors. In our laboratory, we recently observed that MDS/AML erythroblasts display repressive histone modifications and methylation status of PU.1 gene that respond to 5-azacitidine leading to inhibited blast cell proliferation and stimulated myeloid differentiation (Curik N et al. 2012). Inhibition of transcriptional activity of PU.1 protein by GATA-1 has been reported (Nerlov C et al. 2000) however it is not known whether GATA-1 can inhibit PU.1 gene in human early erythroblasts directly. Hypothesis GATA-1 inhibits PU.1 levels directly and modulates its transcriptional outcome in early erythroblasts. We also hypothesize that GATA-1-mediated repression of PU.1 transcription is delayed and this may play a role in ineffective erythropoiesis. Material and Methods Cell lines: MDS-derived OCI-M2 EL and other two human ELs (HEL, K562) and one murine EL (MEL); all co-expressing GATA-1 and PU.1. Patients: MDS patients (N=5) with rather advanced disease; MDS/AML (4) and RAEBI (1). Four received AZA; response: PR (2), SD (2) with HI. Median OS>24 Mo. For chromatin immunoprecipitation (ChIP) analysis either cell lines or CD19/CD3-depleted bone marrow cells were used. Results Direct association of GATA-1 with PU.1 gene was demonstrated in all three human ELs using ChIP. Occupancy of GATA-1 was detected upstream the PU.1 promoter and distally at GATA-1 binding sites or at PU.1 binding sites together with PU.1. Comparable data documenting occupancy of GATA-1 at PU.1 gene were observed also in MEL cells and in normal murine fetal erythroblasts using ChIP-sequencing. To test how GATA-1 regulates PU.1 expression we overexpressed GATA-1 in erythroblasts and tested expression of PU.1, histone H3 modification (near GATA-1 occupancy) and cell growth. We found that GATA-1 inhibited PU.1 expression, facilitated enrichment of repressive modifications at PU.1 gene (H3K9Me, H3K27Me) while depleted activation modifications (H3K9Ac, H3K4Me), and also inhibited cell growth. Next, we tested effects of GATA-1 knockdown using siRNA. Indeed, inhibition of GATA-1 expression in erythroblasts leads to increase in PU.1 level as well as of its targets (CEBPA, MAC1). Using Luciferase assay we confirmed that both endogenously produced PU.1 and GATA-1 are capable to stimulate exogenously inserted reporters. Next, we compared chromatin structure of PU.1 gene between data from ELs, normal controls and high risk MDS. Our data revealed that PU.1 gene in MDS is enriched with repressive modifications (H3K9Me, H3K27Me) while depleted with activation modifications (H3K9Ac, H3K4Me) suggesting defects in dynamic regulation of PU.1 expression in MDS. Conclusion Our data from ELs provide a) evidence of GATA-1-mediated repression of PU.1 gene in erythroblasts and that b) manipulation of GATA-1 affected PU.1 level in opposite direction. In high risk MDS, the chromatin structure of PU.1 gene displays accumulation of repressive epigenetic marks that are responsive to AZA. We think that during early erythroid differentiation GATA-1 binds and represses PU.1 gene, however this is not fully completed in MDS and therefore erythroid differentiation is not efficient. Grants: P301/12/P380, P305/12/1033, NT14174-3/2013, UNCE204021, FR-TI2/509, SVV-2013-266509, PRVOUK-P24/LF1/3 Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document