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  • American Society of Hematology  (16)
  • 1
    Online Resource
    Online Resource
    Gata-Independent Regulation of Red Cell Specific Gene Expression.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1736-1736
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1736-1736
    Abstract: During vertebrate embryonic hematopoiesis, the first blood cells can be identified by expression of the transcription factor genes scl and GATA2, followed by expression of GATA1, a gene required for the erythroid lineage. A high-throughput in situ hybridization screen in zebrafish analyzed the expression pattern of 3700 clones from a hematopoietic cDNA library and discovered 24 genes with expression in the blood. Examination of gene expression in Biklf, GATA1, GATA2, and GATA1/GATA2-deficient animals revealed that most blood genes are dependent upon GATA factors for expression rather than the Krüppel-like transcription factor Biklf. Three novel genes, expressed specifically in erythroid precursors, did not require GATA factors for their expression, demonstrating that some blood genes are regulated in a GATA-independent manner. These three genes were kelch-repeat protein (kelch repeats have been implicated in diverse cellular functions from actin binding to sequestering transcriptions factors), kiaa0650, which contains an SMC-hinge domain, and testhymin, which has no known structural motifs. By using combinations of antisense morpholinos to the known hematopoietic genes biklf , GATA1, GATA2, and scl, we were able to examine the regulation of these novel genes in double and triple knock-down embryos. While expression of kelch-repeat protein was lost in the absence of GATA1 and Biklf, expression of testhymin and kiaa0650 was maintained in GATA1/GATA2/Biklf-deficient embryos, suggesting that these similarly expressed genes are differentially regulated. As with GATA1, kiaa0650 and kelch-repeat protein required Scl for their expression in the early hematopoietic mesoderm while testhymin did not. Furthermore, loss of Scl and GATA2 did not completely ablate testhymin expression, suggesting that this gene is induced by factors upstream or parallel to Scl and GATA2. Taken together, our zebrafish studies establish a regulation of gene expression by a developmental hierarchy of specific transcription factors that act in combination during blood cell maturation.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1736.1736
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    Transcription Factor Induction of Ectopic Vascular Blood Stem Cell Niches In Vivo
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 525-525
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 525-525
    Abstract: The hematopoietic stem and progenitor cell (HSPC) niche is a supportive microenvironment comprised of distinct cell types, including specialized vascular endothelial cells (ECs) that directly interact with HSPCs and promote stem cell function. Utilizing spatial transcriptomics, in combination with tissue-specific RNA-seq, we identified 29 genes selectively enriched in ECs of the zebrafish fetal hematopoietic niche. Using upstream regulatory sequences for two of these genes, mrc1a and selectin E (sele), we generated GFP reporter lines that allowed us to selectively isolate niche ECs for ATAC-seq. This analysis identified 6,848 regions of chromatin that were accessible in niche ECs but not ECs from other tissues. Several of these regions were associated with the 29 genes. To evaluate whether these regions might be enhancers we coupled them to GFP and injected them into embryos. 12/15 sequences drove GFP expression in niche ECs. Upon closer examination of the mrc1a and sele genes, we identified enhancer sequences as short as 125 bp and 158 bp, respectively, which drove niche EC-specific expression. A genome-wide motif enrichment analysis of the 6,848 uniquely open chromatin regions revealed that Ets, SoxF and Nuclear Hormone Receptor (RXRA/NR2F2, specifically) sites were most enriched. In contrast, 4,522 pan-EC elements were enriched for Ets sites but not SoxF or NHR motifs. Using mutant variants of the 125 bp and 158 bp enhancer sequences, we demonstrated that Ets, SoxF and RXRA/NR2F2 sites were independently required for specific transgene expression. Gel shift experiments demonstrated that NR2F2 could bind the 125 bp and 158 bp zebrafish enhancers and this binding was disrupted upon mutation of the NR2F2 binding sites. Knockdown of the endogenous zebrafish nr2f2 gene resulted in a loss of expression of the 125 bp mrc1a enhancer-GFP construct and a significantly reduced number of HSPCs in the fetal niche. We next injected pools of human transcription factors, including at least one member from each of the three families, under the control of a ubiquitous promoter. Strikingly, we found that a combination of ETV2 or ETS1 with SOX7 and NR2F2 generated ectopic patches of mrc1a+ niche ECs that recruited runx1+ HSPCs outside of the endogenous niche. Using high-resolution live cell imaging we could observe HSPCs initially arriving at the ectopic sites, lodging for several hours and then eventually dividing and migrating away from the site through circulation. HSPCs localized to the ectopic regions were found in both intravascular and extravascular spaces, and were often enwrapped by ECs and in contact with cxcl12a+ stromal cells, similar to what is observed in the endogenous niche. Ectopic regions of niche EC gene expression were similarly observed when alternative regulatory elements were used for transcription factor overexpression, including a pan-EC enhancer (nrp1b), a muscle promoter (mylz2) and a heat shock promoter (hsp70). These results suggest the three-factor combinations are sufficient to reprogram niche EC identify in vivo. Lastly, we evaluated by RNA-seq the expression of our niche EC signature in the zebrafish kidney marrow (the site of adult hematopoiesis) and in ECs from multiple organs of the mouse, including the heart, kidney, liver, lung and bone marrow, at multiple stages of development (E11-13, E14-15, E16-17, P2-P4 and adult). Strikingly, 23/29 genes were highly expressed in ECs of the zebrafish kidney and 21/29 genes were enriched in the ECs of a mammalian hematopoietic organ - the fetal liver and/or adult bone marrow - relative to their expression in ECs from non-hematopoietic organs at the same stage. Notably, for a subset of the genes the expression patterns mirrored the temporal dynamics of HSPC ontogeny in the mouse, showing robust expression in fetal liver ECs and then later in adult bone marrow ECs with a concomitant reduction in liver ECs. An analysis of transcription factor expression within these EC populations revealed that Ets1, the SoxF factor Sox18, and Nr2f2 were the most highly expressed members of the Ets, Sox and NHR families. Collectively our work has uncovered a conserved gene expression signature and transcriptional regulatory program unique to the vascular niche of hematopoietic organs. These findings have important implications for designing a synthetic vascular niche for blood stem cells or for modulating the niche in a therapeutic context. Disclosures Zon: Fate Therapeutics: Equity Ownership; Scholar Rock: Equity Ownership; CAMP4: Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-127219
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
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    Pearson marrow pancreas syndrome in patients suspected to have Diamond-Blackfan anemia
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 3 ( 2014-07-17), p. 437-440
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 3 ( 2014-07-17), p. 437-440
    Abstract: PS can be overlooked in the differential diagnosis of children with severe congenital anemia. mtDNA deletion testing should be included in the genetic evaluation of patients with congenital anemia of unclear etiology.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2014-01-545830
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    A Short Pulse of Prostaglandin E2 (PGE2) Induces Long Term Chromatin Changes in Hematopoietic Stem Cells Leading to Increased Self-Renewal and Engraftment
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 246-246
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 246-246
    Abstract: Hematopoietic stem cells (HSCs) offer promising treatment options for many blood diseases. We have previously identified Prostaglandin E2 (PGE2), a small molecule that increased HSC numbers in the zebrafish embryo. In an adult mammalian transplantation setting a two hour treatment significantly enhanced HSC engraftment. Currently PGE2 is being tested in a phase 2 clinical trial to improve cord blood transplants. To better understand PGE2 effect on HSCs mouse multipotent progenitors (MPP), short term (ST) HSCs, and long term (LT) HSCs were isolated via FACS and given a two hour pulse of PGE2 followed by a competitive transplantation assay. Surprisingly, PGE2 treatment mainly affected ST-HSCs by dramatically prolonging their ability to contribute to peripheral blood. The effect of the two hour treatment persisted through secondary competitive transplants in which robust peripheral blood chimerism of ST-HSCs was evident even 1.5 years after having been exposed to the drug. To elucidate underlying molecular changes gene expression right after PGE2 treatment as well as in ST-HSCs after transplantation was assessed. PGE2 target genes were divided into two categories; "transiently induced" and "permanently induced" genes. Most of the transcripts upregulated two hour after PGE2 treatment were "transiently induced" meaning that they did not continue to be differentially expressed after transplantation. In contrast, a few transcripts including chemokines such as Cxcl2, Cxcl3, members of the Fos gene family as well as Nr4a1, 2 and 3 were both upregulated right after PGE2 treatment as well as in ST-HSCs after transplantation. We classified these genes as "permanently induced". ATAC (Assay for Transposase-Accessible Chromatin)-seq analysis of the transplanted PGE2 treated cells indicated that these "permanently induced" genes maintained a distinctly open chromatin profile in both promotor and enhancer regions, whereas the "transiently induced" genes did not. Gene expression in human CD34+ cells included a signature implying CREB as the main transcription factor responsible for the acute PGE2 response. Phospho-FACS in mouse ST-HSCs and Western-blot analysis in human CD34+ cells confirmed a significant increase in CREB phosphorylation after PGE2 stimulation. Chromatin immunoprecipitation (ChIP)-seq analysis of pCREB was able to identify specific genomic regions where pCREB is recruited to after PGE2 treatment. Compared to unstimulated CD34+ cells an increased binding of pCREB could be detected in promotor regions near transcription start sites. In addition over 90% of de-novo pCREB binding occurred in intergenic and intronic regions. To determine the activation state of these putative enhancers changes in the histone mark H3K27ac and open chromatin state (via ATAC-seq) were assessed after PGE2 treatment. The data suggest that PGE2-induced pCREB binding correlates with remodeling of chromatin already after two hours of drug treatment. Furthermore chromatin sites opened by PGE2 were significantly enriched for the CREB motif both in human CD34+ cells acutely after treatment as well as in mouse ST-HSCs 1.5 years after transplant. In summary this work shows that a two hour treatment with PGE2 is sufficient to confer long-term engraftment properties to ST-HSCs. PGE triggers a chromatin remodeling event through CREB that can permanently alter epigenetic state and gene expression of ST-HSCs. Understanding the self-renewal network induced by PGE2 will not only enrich current clinical applications targeted at increasing engraftable HSC numbers but also further basic understanding of HSC self-renewal. Disclosures Zon: FATE Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Scholar Rock: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.246.246
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
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  • 5
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    The Zebrafish Hypochromic Mutant [iItalic]Shiraz[/iItalic] Encodes a Novel Mitochondrial Glutaredoxin That Establishes a Link between Heme and Fe/S Production.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 51-51
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 51-51
    Abstract: Iron is required in the mitochondria both to produce heme, which is used for hemoglobin synthesis, and to make iron-sulfur (Fe/S) clusters, which confer electron transfer or catalytic functions to proteins. Cellular iron utilization and Fe/S cluster production are thought to occur independently, yet the processes are coordinated through currently uncharacterized pathways. The shiraz (sir) zebrafish mutant manifests a hypochromic, microcytic anemia. Positional cloning of sir discovered a deletion at the locus that included the zebrafish orthologue to glutaredoxin 5 (grx5), a gene required in yeast for Fe/S cluster assembly. We found that grx5 is highly expressed in the developing blood and fetal liver of both zebrafish and mouse embryos. Antisense-mediated morpholino knockdown of grx5 prevented hemoglobin production, and overexpression of zebrafish, yeast, mouse, or human grx5 RNA in sir embryos completely rescued hemoglobin production, indicating that grx5 is the gene responsible for the sir phenotype. Expression of zebrafish grx5 was found to rescue Fe/S protein production in the yeast Δgrx5 strain, demonstrating that the role of grx5 in Fe/S cluster assembly is conserved among eukaryotes. The surprising finding that mutating a gene necessary for Fe/S cluster assembly caused a lack of hemoglobin synthesis suggested that we had discovered a connection between these pathways. In vertebrates, iron regulatory protein 1 (IRP1) acts as a sensor of intracellular iron levels and controls cellular iron homeostasis via posttranscriptional regulation of iron uptake, storage, and utilization genes. For instance, IRP1 binds to the 5′ iron response element (IRE) in the aminolevulinate synthase 2 (ALAS2) mRNA, blocking translation when cellular iron is low. However, when cellular iron is replete, IRP1 binds a Fe/S cluster and its RNA-binding activity is abolished. We hypothesized that the loss of Fe/S cluster assembly in sir would activate IRP1 and block ALAS2 synthesis, resulting in hypochromia. In support of this model, overexpression of ALAS2 RNA without the 5′ IRE rescued sir hypochromia, while overexpression of ALAS2 including the IRE did not facilitate rescue. Furthermore, antisense morpholino knockdowns of IRP1 caused rescue of hemoglobin synthesis in sir embryos. The combination of these data indicate that hemoglobin production in the differentiating red cell is monitored through Fe-S cluster assembly as a mechanism to gauge iron levels and accordingly direct heme synthesis. This finding illustrates a crucial role for the mitochondrial Fe/S cluster assembly machinery during hemoglobin production, and has broad implications for the role of such genes in human hypochromic anemias.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.51.51
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
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    Transferrin Acts as an Iron Sensor Upstream of BMP2b in the Zebrafish.
    American Society of Hematology ; 2007
    In:  Blood Vol. 110, No. 11 ( 2007-11-16), p. 704-704
    Details
    In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 704-704
    Abstract: The BMP pathway is important in modulating expression of the iron regulatory hormone hepcidin in response to iron, however how iron levels are sensed is unknown. The zebrafish mutant gavi was identified in a large-scale chemical mutagenesis screen for embryonic anemia. Two alleles were identified: gaviHE067 and gaviIT029, both of which have a homozygous recessive pattern of inheritance. Sequencing of transferrin cDNA from the mutants revealed that each allele of gavi produces an aberrant message and virtually absent transferrin expression. Our previous work demonstrated that hepcidin expression is upregulated following iron dextran injection of the zebrafish embryo. This effect was not impaired by a defect in ferroportin1 (Fraenkel et al., (2005) J Clin Invest115:1532–1541), an iron exporter and ligand for hepcidin. To evaluate the effects of iron loading on transferrin-deficient mutants, gaviIT029 homozygotes at 48 hours post-fertilization were either anesthetized and injected with iron dextran, or anesthetized but not injected. GaviIT029 homozygote embryos exhibited low levels of hepcidin expression that failed to increase following iron injection. Morpholino knockdown of transferrin or transferrin receptor 2 abrogated hepcidin expression, even following iron injection, while knockdown of transferrin receptor 1a (erythroid-specific transferrin receptor 1) or transferrin receptor 1b (a ubiquitously expressed form of transferrin receptor 1) failed to produce this effect. Overexpression of BMP2b, however, rescued hepcidin expression following transferrin knockdown. These findings provide the first evidence that transferrin acts as an in vivo iron sensor upstream of the BMP pathway.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V110.11.704.704
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Derivation of Disease-Free Induced Pluripotent Stem Cells From Patients with Pearson Marrow Pancreas Syndrome
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 3-3
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3-3
    Abstract: Abstract 3 Mutations in mitochondrial DNA (mtDNA) cause several incurable diseases. In congenital mtDNA disorders, a mixture of normal and mutated mtDNA termed heteroplasmy exists at varying levels in different tissues, which determines the severity and phenotypic expression of the disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The clinical hallmarks of PS include sideroblastic anemia and other cytopenias, pancreatic insufficiency, metabolic acidosis, and other systemic organ dysfunction. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Somatic cells can be directly reprogrammed using defined genetic and chemical factors to yield “induced pluripotent stem” (iPS) cells, which have the capacity to differentiate into any tissue. iPS cells are particularly amenable for modeling mtDNA disorders, as cytoplasmic genetic material is retained during reprogramming. We sought to generate iPS cells from patients with PS and related mtDNA disorders to investigate the effects of mitochondrial dysfunction on stem cells and hematopoiesis. From a patient with PS, we generated bone marrow-derived fibroblasts carrying a high heteroplasmic burden of mutant mtDNA, and reprogrammed them into iPS cells. Although reprogramming efficiency was very low and kinetics of iPS colony emergence delayed, PS-iPS cells carrying the pathogenic mutation could be generated and displayed all hallmarks of pluripotency. We observed that PS-iPS cells initially demonstrated slow growth and a propensity for differentiation, but with ongoing passage in tissue culture, these characteristics improved. Unexpectedly, we found that the proportion of mutant mtDNA decreased rapidly in the PS-iPS lines as a function of passage. By subcloning, we were able to generate iPS cell lines with virtually undetectable amounts of mutant mtDNA, but which retained a viral integration pattern confirming their nuclear genetic identity to the original, highly heteroplasmic iPS clone. From “purged” PS-iPS cells, we generated hematopoietic progenitors free of detectable mutant mtDNA, thus yielding genetically identical, disease-free iPS cells and blood cells from a patient with Pearson syndrome. Disease-free iPS cells were readily obtained from the skin-derived fibroblasts of two other patients that carried a lower burden of mutant mtDNA. Our results suggest that mitochondrial dysfunction drives the segregation or elimination of mutant mtDNA in iPS cells as a function of passage, implying that maintenance of self-renewal and pluripotency are highly dependent on intact mitochondrial function. Importantly, a similar depletion of mutant mtDNA can be observed over time in vivo in certain tissues, such as hematopoietic cells, of patients with PS and other mtDNA disorders. This work provides a unique set of in vitro cellular models carrying varying degrees of mtDNA heteroplasmy to interrogate the effects of mitochondrial dysfunction on hematopoiesis. PS-iPS cells also provide a valuable opportunity to determine the factors driving changes in mtDNA heteroplasmy in stem cells, which holds important therapeutic implications for PS and a variety of congenital and acquired mtDNA disorders. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.3.3
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4997-4997
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4997-4997
    Abstract: Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding . Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years; incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p & lt;0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality; the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. Figure 1 Figure 1. Disclosures Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Tempus: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tempus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dendreon: Consultancy; Caris: Other: Serves as a molecular tumor board ; Vividion: Consultancy; Sorrento Therapeutics: Consultancy; Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria; CSL Behring: Research Funding; Alnylam: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-154314
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 9
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    Activity of mRNA COVID-19 vaccines in patients with lymphoid malignancies
    American Society of Hematology ; 2021
    In:  Blood Advances Vol. 5, No. 16 ( 2021-08-24), p. 3062-3065
    Details
    In: Blood Advances, American Society of Hematology, Vol. 5, No. 16 ( 2021-08-24), p. 3062-3065
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    URL: Article
    DOI: 10.1182/bloodadvances.2021005328
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 2876449-3
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  • 10
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    Frascati , a Mitochondrial Solute Transporter, and Its Role in Vertebrate Erythropoiesis.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 49-49
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 49-49
    Abstract: Acquired and congenital defects in iron metabolism from either deficiency or excess are one of the most common human diseases. Here we present the characterization of the zebrafish frascati mutation, which results in a profound hypochromic anemia and a developmental arrest at the pro-erythroblast stage. Using a positional cloning strategy, we have identified the gene disrupted frascati in mutants as a novel member of the mitochondrial solute transporter family. Members of this family of solute carriers have related tripartite sequence and structure. They function in transporting various metabolites and substrates across the inner mitochondrial membrane. We have verified the identity of the gene in zebrafish by the following criteria: (a) tissue-restricted expression in erythroid progenitors, (b) identification of missense mutations from the frascati five alleles, (c) rescue of anemia by over-expression frascati of cRNA in mutant embryos, and (d) mimicry of anemia using inactivating antisense morpholinos in wildtype embryos. We have also identified the functional ortholog in the mouse which has an analogous tissue and developmental expression pattern. The frascati ortholog in the mouse is highly expressed in fetal liver and adult bone marrow and spleen. The murine frascati transcript and protein are induced during terminal erythroid differentiation in MEL cells treated with either DMSO or HMBA. The over-expression of the mouse frascati cRNA in zebrafish frascati mutant embryos rescued their anemia with equal efficacy as the zebrafish clone. Given the identity of the gene and the requirement for iron in heme biosynthesis in the mitochondria of the developing erythron, we injected exogenous iron-dextran into frascati embryos. The embryos injected with iron-dextran were allowed to develop to 3 days post-fertilization, then stained for hemoglobinized cells with o-dianisidine and genotyped. Using this assay, the anemia caused by frascati the mutation could be partially rescued with exogenous iron supplementation. We therefore propose that the frascati gene functions as the essential transporter for iron importation into the mitochondria for heme biosynthesis and subsequent hemoglobin production in developing erythroid progenitors. Insight into the function of frascati the gene will be directly relevant to our understanding of human disorders of iron deficiency anemia and iron-overload sideroblastic anemia.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.49.49
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
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