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  • 1
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    Online Resource
    Epoxyeicosatrienoic Acids Regulate Hematopoietic Stem/Progenitor Cell Fate Decision During Stress Response and Embryonic Hematopoiesis
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 860-860
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 860-860
    Abstract: Abstract 860 During bone marrow transplantation, hematopoietic stem/progenitor cells (HSPCs) are exposed to various stress signals, and undergo homing, rapid proliferation and differentiation in order to achieve engraftment. To explore how fate decisions are made under such stress conditions, we developed a novel imaging-based competitive marrow transplantation in zebrafish. The feasibility of handling hundreds of zebrafish for transplantation per day allowed us to screen a library of 480 small molecules with known bioactivity, aimed at identifying new drugs and pathways regulating HSPC engraftment. Two structurally related eicosanoids, 11,12-epoxyeicosatrienoic acid (EET) and 14,15-EET, were able to enhance GFP+ marrow engraftment compared to DsRed2+ engraftment in zebrafish. This remarkable effect of EETs on adult marrow prompted us to study the effect of EETs in embryonic hematopoiesis. Treating zebrafish embryos with 11,12-EET during definitive hematopoiesis increased the HSPC marker Runx1 expression in the AGM (Aorta-Gonad-Mesonephros), resulting in a significant increase of HSPC in the next hematopoietic site, caudal hematopoietic tissue, the equivalent of fetal liver/placenta in mammals. The same treatment condition also induced ectopic Runx1 expression in the tail mesenchyme, a non-hematopoietic tissue. Microarray analysis on EET-treated zebrafish embryos revealed an upregulation of genes involved in stress response, especially Activator Protein 1 (AP-1) family members. Genetic knockdown experiments confirmed AP-1 members, especially JunB and its binding partners, cFos and Fosl2, are required for Runx1 induction. Motif analysis also predicted several conserved AP-1 binding sites in the Runx1 enhancer regions. To understand how EETs induced AP-1 expression, a suppressor screen was performed in zebrafish embryos. The screen revealed that activation of both PI3K/Akt and Stat3 are required for induced AP-1 expression, and therefore Runx1 upregulation. Similarly, ex vivo treatment of mouse whole bone marrow with 11,12-EET resulted in a 2-fold increase of long-term repopulating units. Microarray data had previously shown that Cyp2j6, one of the cytochrome P450 enzymes involved in EET biosynthesis from arachidonic acid, is enriched in quiescent mouse long-term HSCs. To further increase the EET levels in HSPCs, human CYP2C8 enzyme was over-expressed in transgenic mice using the Tie2 promoter. These transgenic mice have a 4-fold increase of long-term multi-lineage repopulating unit compared to their wild-type siblings. In purified mouse HSPCs, EETs directly and cell-autonomously activate PI3K/AKT pathway. Co-treatment of mouse bone marrow with EET and a PI3K inhibitor, LY294,002, completely blocked EET-induced enhancement of mouse bone marrow engraftment. In conclusion, we performed the first competitive marrow transplantation-based chemical screen, leading to the discovery of arachidonic acid-cytochrome P450-EETs as a novel modulator of HSC cell fate decision. PI3K/Akt and Stat3 pathways activated by EETs are required for adult HSPC engraftment and/or embryonic HSC specification, partially through transcriptional regulation of AP-1. We also demonstrated the requirement of AP-1 family members for Runx1 expression during embryonic development. This discovery may have clinical application in marrow or cord blood transplantation. Disclosures: Daley: iPierian, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Verastem, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Solasia, KK: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; MPM Capital, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Zon:Fate Therapeutics: Founder; Stemgent: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.860.860
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 2
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    Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs During Differentiation and Regeneration,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3387-3387
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3387-3387
    Abstract: Abstract 3387 BMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we have evaluated their function during hematopoietic regeneration after irradiation. Using heat-shock inducible transgenic zebrafish lines that overexpress BMP2 or Wnt8, we demonstrated accelerated marrow recovery following irradiation. Heat-shock induced overexpression of the respective inhibitors Chordin and DKK1 blunted the recovery. Surprisingly, gene expression profiling after induction of BMP or Wnt signaling in zebrafish marrow cells post-irradiation revealed increased expression of the key hematopoietic genes scl, runx1, and gata2. To determine if the effect of BMP and Wnt signaling on hematopoietic genes during regeneration was direct, we performed ChIP-PCR for Smad1 and the hematopoietic regulator Gata2 in murine lineage-negative progenitors seven days after a sublethal irradiation. We found that Smad1 and Gata2 co-occupy hematopoietic genes including Cd9, Il13, Mapk6, and Meis1. To examine the binding of SMAD1 and TCF7L2 throughout the genome of hematopoietic cells, we employed ChIP-seq in human erythroid and myeloid leukemia cell lines, K562 and U937, respectively. More than 70% of the genes bound by SMAD1 and TCF7L2 were co-occupied with the lineage transcription factors GATA1 and GATA2 in erythroid cells, and with C/EBPα in myeloid cells. This finding suggests that signaling transcription factors control hematopoietic gene programs by binding DNA adjacent to lineage-specific transcription factors. The transcriptional output of BMP and Wnt activity was tested on an LMO2 enhancer reporter construct. Expression of SMAD1 or TCF7L2 alone had little effect, but markedly increased reporter activity in conjunction with GATA2, indicating that BMP and Wnt signaling cooperate with lineage regulators to enhance transcription of cell-type specific target genes. To establish the order of transcription factor occupancy, we utilized estrogen-inducible C/EBPα-ER in K562 cells or GATA1 induction in murine G1ER cell lines, and assessed SMAD1 occupancy before and after induction of each respective lineage regulator. Induction of the myeloid lineage regulator C/EBPα in K562 cells shifted binding of SMAD1, such that SMAD1 co-occupancy with C/EBPα changed from 6% to 15% of C/EBPα targets. In contrast, expression of the erythroid regulator GATA1 promoted loss of SMAD1 on 82% of its targets, and restricted more than 98% of the remaining SMAD1 sites to erythroid targets adjacent to GATA1. Co-occupancy of signaling factors and lineage regulators was further tested in primary human CD34+ multipotent hematopoietic progenitors and CD34+ cells directed to the erythroid lineage. Both SMAD1 and TCF7L2 co-localized with GATA2 on greater than 75% of bound genes in multipotent CD34+ progenitor cells. Similar to our results following GATA1 induction in G1ER cells, SMAD1 occupancy shifted to 65% erythroid targets upon differentiation of progenitors to the erythroid lineage. These data provide strong evidence that the binding of signaling factors follows the genomic occupancy of the dominant lineage regulator during differentiation. Together, our findings demonstrate that hematopoietic regeneration is driven by collaboration of master regulators and signaling transcription factors to control the entire hematopoietic program. Disclosures: Daley: Verastem, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; iPierian, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Epizyme, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Solasia, KK: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; MPM Capital, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Zon:Fate Therapeutics:; Stemgent: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3387.3387
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Excessive R-Loops Trigger an Inflammatory Cascade Leading to Aberrant Hematopoietic Stem and Progenitor Cell Expansion
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 772-772
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 772-772
    Abstract: Mutations in DEAD-box Helicase 41 (DDX41) are observed in patients with myelodysplastic syndromes (MDS) with inferior overall survival, implicating this factor in disease pathogenesis. DDX41 is an understudied factor with links to inflammation and RNA processing, but whose function in hematopoiesis is unknown. Using a novel zebrafish model of Ddx41-deficiency, we unveiled a critical role for Ddx41 in regulating hematopoietic stem and progenitor cells (HSPCs). Mutants for ddx41 have more HSPCs than their siblings as measured by in situ hybridization for the HSPC marker runx1 as well as quantification of cd41:gfp+ and runx1:mcherry+ HSPCs by flow cytometry. To uncover potential mechanisms driving HSPC expansion in ddx41 mutants, we performed RNA-seq analysis of purified HSPCs from ddx41 mutants and sibling controls. Expression of inflammatory target genes was significantly elevated in ddx41 mutants including those regulated by the transcription factor NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells). As inflammatory signaling and NFκB signaling in particular is elevated in MDS, we next explored Ddx41 regulation of NFκB signaling. Using an in vivonfkb:gfp reporter, we demonstrated that NFκB signaling was indeed elevated in ddx41 mutants. DDX41 is implicated in the STING (STimulator of INterferon Genes) and TBK1 (TANK binding kinase 1) pathway that mediates type I interferon production in response to foreign or damaged endogenous DNAs. By lowering pathway activity via knockdown of sting or pharmacological inhibition of TBK1, we determined that the STING/TBK1 pathway triggered excessive NFκB activation in ddx41 mutants. Moreover, the elevated inflammatory signaling was detrimental to normal HSPC homeostasis as lowering STING/TBK1 pathway activation significantly reduced HSPC expansion in ddx41 mutants, as measured by runx1in situ hybridization and cd41:gfp flow cytometric quantification. R-loops, nucleic acid structures consisting of RNA:DNA hybrids and displaced ssDNAs, can activate the STING/TBK1 pathway via the nucleic acid sensor cGAS (cyclic GMP-AMP synthase). Recent proteomic analysis showed that DDX41 can bind R-loops. Via immunofluorescence quantification of RNA:DNA hybrid levels in ddx41 mutants versus sibling controls, we revealed that Ddx41 acts as a suppressor of R-loop accumulation. Using a RNASEH1-GFP transgenic zebrafish line that permits inducible depletion of R-loops, we revealed that excess R-loops in ddx41 mutants promote HSPC expansion as measured by runx1in situ hybridization and runx1:mcherry flow cytometric quantification. Moreover, using RT-qPCR analysis of NFκB target genes, we determined that R-loop depletion dampened NFκB activation in ddx41 mutants, suggesting the R-loop-mediated effects on HSPC numbers was via inflammatory signaling. We deciphered cGAS activity was critical for this effect as both nfkb:gfp reporter activity and HSPC levels in ddx41 mutants were diminished following treatment with a pharmacological inhibitor of cGAS. Our data demonstrate that DDX41 insufficiency triggers an R-loop-mediated inflammatory cascade leading to aberrant HSPC expansion and is the first study to delineate a functional consequence for R-loops in HSPC biology. Furthermore, recent studies showed R-loop accumulation in other common forms of MDS suggesting our novel in vivo findings are more broadly applicable to the MDS pathogenesis. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-124888
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 4
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    Distinct Signaling Centers Define Stages of Human Erythropoiesis and Harbor Common Variations of Red Blood Cell Traits
    American Society of Hematology ; 2017
    In:  Blood Vol. 130, No. Suppl_1 ( 2017-12-07), p. 773-773
    Details
    In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 773-773
    Abstract: Single Nucleotide Polymorphisms (SNPs) identified through genome-wide association studies (GWAS) could provide insight into the mechanism of human genetic diseases. Here we have studied SNPs that are associated with six critical red blood cell traits - hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). During erythroid differentiation of human CD34+ cells, we mapped enhancers and open chromatin regions by H3K27Ac ChIPseq and ATACseq, and studied the SNPs that reside within these DNA regulatory elements. We followed genomic binding of lineage restricted GATA transcription factors and BMP signal responsive transcription factor SMAD1 in CD34+ cells during erythropoiesis. By overlapping their genomic occupancy with stage-matched RNAseq, we found that SMAD1, in association with GATA-factors, serves as marker of genes responsible for differentiation at every step of differentiation. ATACseq and H3K27Ac patterns demonstrated that GATA+SMAD1 co-occupied regions correlate with open chromatin and super enhancers at every stage, whereas GATA-only regions are associated with genes with low/basal level of expression during differentiation. ChIPseq for other crucial signaling transcription factors, such as cAMP-responsive and TGFb-responsive factors (CREB and SMAD2, respectively) demonstrated a remarkable co-existence of such factors at GATA+SMAD1 co-bound regions nearby stage-specific genes. We defined such regions as "signaling centers" where multiple signaling transcription factors converge with master transcription factors to determine optimum stage-specific gene expression in response to growth factors. Surprisingly, we observed that while only 15% of RBC-SNPs target blood-master-transcription-factor motifs, at least 70% of them reside on various signaling pathway associated transcription factor motifs including SMADs (BMP/TGFβ signaling), RXR/ROR (nuclear receptor signaling), FOXO/FOXA (FOX signaling), CREBs (cAMP signaling) and TCF7L2 (WNT signaling). Our bioinformatics-algorithms demonstrated that, in contrast to GATA-only sites, SMAD1+GATA co-bound signaling centers harbor cis -acting motifs and display enriched binding of cell-type specific transcription factors (e.g. PU1 and FLI1 in progenitor vs. KLF1 and NFE2 in differentiated cells). Such distinct identities of signaling centers could serve as codes to distinguish progenitor-specific genes from erythroid-specific genes, and govern their stage-specific expression. We performed CRISPR-CAS9 mediated perturbations of each of the PU1, GATA and SMAD1 motifs separately in a representative progenitor signaling center in K562 cells. Similar to loss of PU1 and GATA motifs, loss of SMAD1 motif selectively inhibited expression of the associated gene. This suggests a signaling factor SMAD1 is important within signaling centers to obtain optimum gene expression. Moreover, a progenitor factor PU1 direct binding of SMAD1 to progenitor-specific signaling centers since with overexpression of PU1 in K562 cells, SMAD1 occupancy was concomitantly increased in selective genomic regions where PU1 binding was increased. More than 80% of the RBC-trait-SNPs are enriched within SMAD1-bound signaling centers. Such SNPs either destroy or create new signaling factor binding sites, e.g. SMAD motifs. We validated one such SNP associated with the MCV-trait near HIST1H4A, agene that increases in expression during differentiation. Using gel-shift assay, we found that SMAD1 binding is compromised when the major allele T changes to minor allele A under MCV-trait. Remarkably, eQTL analysis using microarray gene expression profiles of peripheral blood obtained from the Framingham Heart Studies revealed that expression of HIST1H4A is significantly more in a population with T-allele than that with A-allele. This demonstrates that inhibition of SMAD1 binding by the SNP causes a loss of allele-specific HIST1H4A expression. Taken together, our study provides the first evidence that naturally occurring GWAS variations directly impact gene expression from signaling centers by modulating binding of signaling transcription factors. Such aberrant signaling events over time could lead to "signalopathies", ultimately resulting in phenotypic variations of RBC traits. Disclosures Zon: Fate, Inc.: Consultancy, Equity Ownership; Marauder, Inc.: Consultancy, Equity Ownership; Scholar Rock, Inc: Consultancy, Equity Ownership; Stemgent: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V130.Suppl_1.773.773
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2017
    detail.hit.zdb_id: 1468538-3
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  • 5
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    DDX41-associated susceptibility to myeloid neoplasms
    American Society of Hematology ; 2023
    In:  Blood Vol. 141, No. 13 ( 2023-03-30), p. 1544-1552
    Details
    In: Blood, American Society of Hematology, Vol. 141, No. 13 ( 2023-03-30), p. 1544-1552
    Abstract: Deleterious germ line DDX41 variants confer risk for myeloid neoplasms (MNs) and less frequently for lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germ line DDX41 variants include truncating alleles that comprise about two-thirds of all alleles, missense variants located preferentially within the DEAD-box domain, and deletion variants. The identification of a truncating allele on tumor-based molecular profiling should prompt germ line genetic testing because & gt;95% of such alleles are germ line. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germ line DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germ line DDX41 alleles are noteworthy: (1) certain variants are common in particular populations, (2) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people, (3) despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis, and (4) individuals with deleterious germ line DDX41 variants develop acute severe graft-versus-host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive posttransplant cyclophosphamide, suggesting a proinflammatory milieu that stimulates donor-derived T cells. Biochemical studies and animal models have identified DDX41’s ability to interact with double-stranded DNA and RNA:DNA hybrids with roles in messenger RNA splicing, ribosomal RNAs or small nucleolar RNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2022017715
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
    detail.hit.zdb_id: 1468538-3
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  • 6
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    Association Between Downregulation of POT1 Expression and Chromosome 7 Deletion, Response to Hypomethylation Agent Treatment, and Patient Survival in Myelodysplastic Syndromes
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 4663-4663
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4663-4663
    Abstract: The POT1 gene is located in chromosome 7 and encodes a key component of the shelterin complex, which is essential for the maintenance of telomere and chromosome integrity. Somatic mutations of POT1 have been identified in chronic lymphocytic leukemia, which indicates that POT1 dysfunction is involved in the pathogenesis of hematological neoplasms. At the same time, abnormal telomere shortening has been observed in MDS/AML and a spectrum of bone marrow failure syndromes. We therefore sought to study the potential role of POT1 in MDS by sequencing the gene and characterizing its expression in primary bone marrow specimens of patients with MDS. We first sequenced all POT1 coding regions that are known to have mutations in CLL. PCR-Sanger sequencing was performed in bone marrow mononuclear cells (BM-MNNC) of a cohort of 30 patients with MDS (15 with RAEB/RAEBT, 11 with RA/RARS/RCMD/MDS-U, 2 with CMML, and 2 with 5q- syndromes). No genetic mutations in the POT1 gene were detected. This result suggests that genetic alteration of POT1 is rare in MDS. We then evaluated the expression of POT1 using cDNA arrays (n=183) or RT-PCR (n=58) in a cohort of 241 patients with MDS from two centers. The median age of our patients was 71 years (32-95). Diagnoses included RAEB in 108 (45%), 5q- syndrome in 18 (8%), and other syndromes (RA, RCMD, and MDS-U) in 115 (47%) cases. In this cohort, 140 (58%) patients were diploid, 22 (9%) had chromosome 7 alterations, 21 (9%) had 5q deletion, and 58 (24%) had other cytogenetic abnormalities. Results indicate that POT1 was underexpressed (less than 50% of the POT1 level in normal controls) in the bone marrow CD34+ hematopoietic progenitor cell population in 138 patients (57%). However, no significant difference was observed between the whole MDS cohort and control BM CD34+ cells from healthy donors (n=25). Further subset analysis based on karyotypes revealed that 81% of patients with chromosome 7 alterations (7- and 7q-) had lower expression of POT1 versus 38% of diploid patients, 35% of 5q patients, and 42% of patients with other cytogenetic alterations (p=0.001). ANOVA testing indicated that expression of POT1 was significantly downregulated (less than 50% of control) only in patients with chromosome 7 alteration (p 〈 0.000) but not in other cytogenetic subsets. When we compared the survival of patients with POT1 downregulation to other groups, we observed a strong tendency toward shorter overall survival in patients with POT1 downregulation (median OS of 37 months [95% CI: 21-52] vs 53 months [95%CI: 30-75] ; p=0.139). This tendency toward poorer OS was also observed when we excluded cases with chromosome 7 alterations (37 months [95% CI: 17-57] vs 53 months [95%CI: 25-80] ; p=0.186). Next, we evaluated the potential impact of POT1 expression on responses to therapies. In the subgroup of patients with available treatment records for analysis (n=58), a total of 42 patients received hypomethylating agents (HMA), and 47% of them achieved responses. When comparing POT1 expression levels to HMA response, we observed significantly lower POT1 expression in HMA non-responders than in responders (U Mann-Whitney test p= 0.028). In a regression model for response to HMA, we also observed that downregulation of POT1 was associated with a poorer response to HMA (OR 4.96 [1.01-24.37]; p=0.049). However, when we introduced chromosome 7 alterations into the model, POT1 expression lost its effect, which suggests that the impact of POT1 on response to HMA is due to its interaction with chromosome 7 alterations. Taken together, the results of this study indicate that the downregulation of POT1 gene expression, which is related to chromosome 7 deletions, may play a role in the pathogenesis and prognosis of MDS, including response to HMA-based therapies. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.4663.4663
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 7
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    The Spliceosomal Component Sf3b1 Is Essential for Hematopoietic Differentiation
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 3582-3582
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3582-3582
    Abstract: Myelodysplastic syndrome (MDS) is a disorder arising from hematopoietic stem and progenitor cell (HSPC) dysfunction resulting in ineffective hematopoiesis. A multitude of recurrent somatic mutations in spliceosomal components were recently identified in MDS that likely contribute to the pathogenesis of the disease. The lack of in vivo models to study cell-type specific effects of spliceosomal mutations limits our understanding of why such mutations lead to hematopoietic abnormalities. Using a zebrafish with a loss-of-function mutation in sf3b1 (sf3b1hi3394), an essential member of the spliceosome, we demonstrate hematopoietic cell differentiation and hematopoietic stem and progenitor cell (HSPC) specification are processes sensitive to spliceosomal malfunction. Primitive erythropoiesis initiates normally in sf3b1 mutants as evidenced by expression of scl in the posterior lateral plate mesoderm at 14 hours post fertilization (hpf) as well as gata1 and beta-globin at 24 hpf. Flow cytometry quantification of gata1:gfp positive erythrocytes showed sf3b1 mutants have 25% more cells at 24 hpf, but greater than 3-fold fewer cells at 36 and 48 hpf, time points when wild type erythroblasts are expanding and differentiating. At 48 hpf, we also observed decreased levels of o-dianisidine positive erythrocytes, low numbers of morphologically mature erythroblasts, and higher levels of immature erythroblasts in sf3b1 mutants. Similarly, we observed normal initiation of primitive myelopoiesis marked by stem cell leukemia (scl) expression in the anterior lateral plate mesoderm at 14 hpf, but diminished expression of more differentiated markers, l-plastin and myeloperoxidase at 24 and 28 hpf in sf3b1 mutants. Quantification of lysozyme C:dsred positivemyeloid cells using flow cytometry also showed 24-fold fewer mature myeloid cells in sf3b1 mutants at 36 hpf. Our data on primitive erythropoiesis and myelopoiesis indicate sf3b1 is required for hematopoietic cell differentiation. Additionally, sf3b1 mutants have diminished expression of the definitive HSPC marker runx1 within the aorta at 28 hpf. In contrast, we observed normal expression of the pan-endothelial marker kinase insert domain receptor-like (kdrl) and aorta-specific markers notch1b and notch3 at 24 hpf. Flow cytometry quantification of kdrl:gfp endothelial cells at 24 hpf shows no difference in the frequency of endothelial cells in sf3b1 mutants. Moreover, we observed fewer cmyb:gfp; kdrl:dsred double positive HSPCs along the dorsal aorta. The data suggest that decreased HSPC formation in sf3b1 mutants is due to a failure in hemogenic induction. From these studies, we show sf3b1 is required at specific stages of hematopoietic cell development. These results provide novel insight into the role of splicing in blood cell development, and can afford a deeper understanding of the mechanism of splicing regulation on the origins of MDS. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.3582.3582
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 8
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    From the bedside to the bench: new discoveries on blood cell fate and function
    Elsevier BV ; 2017
    In:  Experimental Hematology Vol. 47 ( 2017-03), p. 24-30
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    In: Experimental Hematology, Elsevier BV, Vol. 47 ( 2017-03), p. 24-30
    Type of Medium: Online Resource
    ISSN: 0301-472X
    URL: Article
    DOI: 10.1016/j.exphem.2016.11.007
    RVK:
    XA 42470
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2017
    detail.hit.zdb_id: 2005403-8
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  • 9
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    BMP and Wnt Specify Hematopoietic Fate by Activation of the Cdx-Hox Pathway
    Elsevier BV ; 2008
    In:  Cell Stem Cell Vol. 2, No. 1 ( 2008-01), p. 72-82
    Details
    In: Cell Stem Cell, Elsevier BV, Vol. 2, No. 1 ( 2008-01), p. 72-82
    Type of Medium: Online Resource
    ISSN: 1934-5909
    URL: Article
    DOI: 10.1016/j.stem.2007.10.022
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 2375356-0
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  • 10
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    Hematopoietic Fingerprints: An Expression Database of Stem Cells and Their Progeny
    Elsevier BV ; 2007
    In:  Cell Stem Cell Vol. 1, No. 5 ( 2007-11), p. 578-591
    Details
    In: Cell Stem Cell, Elsevier BV, Vol. 1, No. 5 ( 2007-11), p. 578-591
    Type of Medium: Online Resource
    ISSN: 1934-5909
    URL: Article
    DOI: 10.1016/j.stem.2007.10.003
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2007
    detail.hit.zdb_id: 2375356-0
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