FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3041744102> ?p ?o ?g. }

• W3041744102 endingPage "606" @default.
• W3041744102 startingPage "606" @default.
• W3041744102 abstract "Abstract Lentiviral vectors have been used for the delivery of genetic material into hematopoietic stem and progenitor cells (HSPC) in over 100 patients enrolled in clinical trials worldwide. Lentiviral vectors, in contrast to γ-retroviral vectors, have not been associated with insertion site-associated malignant clonal expansions, and thus have been considered safer for use in HSC gene therapies. Here, however, we present a case of abberant, markedly dysplastic clonal hematopoiesis impacting the erythroid, myeloid and megakaryocytic lineages in a rhesus macaque transplanted with lentivirally barcoded hematopoietic stem and progenitor cells. Autologous CD34+ HPSC from macaque ZL34 were transduced with a highly diverse lentiviral barcoded library and reinfused following total body irradiation. The lentiviral vector contained a copGFP reporter gene and a murine stem-cell virus (MSCV) promoter. Transduction parameters (MOI:25) and cell dose (5.4 * 106 CD34+ cells/kg, 27.1% GFP+ infusate) were similar to those of 14 other macaques transplanted with the identical or similar barcoded lentiviral vectors that manifested highly polyclonal (thousands clones/animal) and stable hematopoiesis following transplantation (Koelle, Blood 2017; Wu Cell Stem Cell, 2014). ZL34 initially engrafted with normal kinetics and blood count recovery. However, beginning 4-5 months (m) post-transplant, increased numbers of eosinophils were noted in the blood, and platelet counts decreased from the normal range to less than 30,000/uL. By 7m, strikingly elevated numbers of nucleated red blood cells (nRBCs) appeared in the blood, persisting at levels of up to 6000/uL up to the present, 16m post-transplant. Fetal hemoglobin levels were markedly increased to >76% as determined by HPLC. The bone marrow was hypercellular and markedly dysplastic, with uninuclear/small megakaryoctyes, erythroid predominance, and a left-shift in all lineages but no increased blasts. Karyotype was normal. Barcode retrieval from purified blood myeloid, T, B, NK and nRB cell populations via low cycle PCR and Illumina sequencing revealed marked clonal dominance of 7 barcodes in the nRBC lineage and in the dysplastic myeloid lineages beginning at 5 months post-transplant. All 7 barcodes were confirmed to be present in the abnormal clone by CFU assays. High-throughput insertion site retrieval followed by insertion-specific PCR assay matched 6 barcodes to insertions, uncovered two additional mutated barcodes in the dominant clone not previously retrieved, and thus so far confirm 8-9 insertions in the dominant nRBC/myeloid clone. These insertions are adjacent to or within several potential genes of interest given the phenotype, including KITLG (SCF) and PLAG1. Bulk and single cell RNA-seq studies are being performed to uncover putative insertion-mediated upregulation or downregulation of genes near the 8 dominant integration sites. In conjunction with our previous barcoding studies and unpublished erythropoiesis studies, these results suggest that lentiviral insertion(s) into an HSPC resulted in clonal expansion, markedly abnormal myeloid and erythroid proliferation and differentiation, and a profoundly abnormal myeloproliferative/myelodysplastic phenotype. As this is possibly the first clear case of a lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal HSPC, these results are concerning, and suggest that other methods such as targeted gene correction are important to pursue for gene therapy of bone marrow diseases. Disclosures Dunbar: Novartis/GSK to institute: Research Funding." @default.
• W3041744102 created "2020-07-16" @default.
• W3041744102 creator A5000749752 @default.
• W3041744102 creator A5001134935 @default.
• W3041744102 creator A5010311406 @default.
• W3041744102 creator A5016687319 @default.
• W3041744102 creator A5019094447 @default.
• W3041744102 creator A5020688388 @default.
• W3041744102 creator A5021605414 @default.
• W3041744102 creator A5031734294 @default.
• W3041744102 creator A5032471296 @default.
• W3041744102 creator A5044681793 @default.
• W3041744102 creator A5056272315 @default.
• W3041744102 creator A5060636006 @default.
• W3041744102 creator A5060825554 @default.
• W3041744102 creator A5063668393 @default.
• W3041744102 creator A5075578073 @default.
• W3041744102 creator A5081737757 @default.
• W3041744102 creator A5086721472 @default.
• W3041744102 creator A5086735998 @default.
• W3041744102 date "2017-12-07" @default.
• W3041744102 modified "2023-10-01" @default.
• W3041744102 title "Aberrant Clonal Hematopoiesis of the Erythroid and Myeloid Lineages in a Lentivirally Barcoded Rhesus Macaque" @default.
• W3041744102 doi "https://doi.org/10.1182/blood.v130.suppl_1.606.606" @default.
• W3041744102 hasPublicationYear "2017" @default.
• W3041744102 type Work @default.
• W3041744102 sameAs 3041744102 @default.
• W3041744102 citedByCount "0" @default.
• W3041744102 crossrefType "journal-article" @default.
• W3041744102 hasAuthorship W3041744102A5000749752 @default.
• W3041744102 hasAuthorship W3041744102A5001134935 @default.
• W3041744102 hasAuthorship W3041744102A5010311406 @default.
• W3041744102 hasAuthorship W3041744102A5016687319 @default.
• W3041744102 hasAuthorship W3041744102A5019094447 @default.
• W3041744102 hasAuthorship W3041744102A5020688388 @default.
• W3041744102 hasAuthorship W3041744102A5021605414 @default.
• W3041744102 hasAuthorship W3041744102A5031734294 @default.
• W3041744102 hasAuthorship W3041744102A5032471296 @default.
• W3041744102 hasAuthorship W3041744102A5044681793 @default.
• W3041744102 hasAuthorship W3041744102A5056272315 @default.
• W3041744102 hasAuthorship W3041744102A5060636006 @default.
• W3041744102 hasAuthorship W3041744102A5060825554 @default.
• W3041744102 hasAuthorship W3041744102A5063668393 @default.
• W3041744102 hasAuthorship W3041744102A5075578073 @default.
• W3041744102 hasAuthorship W3041744102A5081737757 @default.
• W3041744102 hasAuthorship W3041744102A5086721472 @default.
• W3041744102 hasAuthorship W3041744102A5086735998 @default.
• W3041744102 hasConcept C10205521 @default.
• W3041744102 hasConcept C104317684 @default.
• W3041744102 hasConcept C109159458 @default.
• W3041744102 hasConcept C126322002 @default.
• W3041744102 hasConcept C159047783 @default.
• W3041744102 hasConcept C169760540 @default.
• W3041744102 hasConcept C201750760 @default.
• W3041744102 hasConcept C203014093 @default.
• W3041744102 hasConcept C2778086970 @default.
• W3041744102 hasConcept C2778950215 @default.
• W3041744102 hasConcept C2779175743 @default.
• W3041744102 hasConcept C2779282312 @default.
• W3041744102 hasConcept C28328180 @default.
• W3041744102 hasConcept C2911091166 @default.
• W3041744102 hasConcept C32470452 @default.
• W3041744102 hasConcept C40767141 @default.
• W3041744102 hasConcept C502942594 @default.
• W3041744102 hasConcept C54355233 @default.
• W3041744102 hasConcept C71924100 @default.
• W3041744102 hasConcept C86803240 @default.
• W3041744102 hasConcept C95444343 @default.
• W3041744102 hasConceptScore W3041744102C10205521 @default.
• W3041744102 hasConceptScore W3041744102C104317684 @default.
• W3041744102 hasConceptScore W3041744102C109159458 @default.
• W3041744102 hasConceptScore W3041744102C126322002 @default.
• W3041744102 hasConceptScore W3041744102C159047783 @default.
• W3041744102 hasConceptScore W3041744102C169760540 @default.
• W3041744102 hasConceptScore W3041744102C201750760 @default.
• W3041744102 hasConceptScore W3041744102C203014093 @default.
• W3041744102 hasConceptScore W3041744102C2778086970 @default.
• W3041744102 hasConceptScore W3041744102C2778950215 @default.
• W3041744102 hasConceptScore W3041744102C2779175743 @default.
• W3041744102 hasConceptScore W3041744102C2779282312 @default.
• W3041744102 hasConceptScore W3041744102C28328180 @default.
• W3041744102 hasConceptScore W3041744102C2911091166 @default.
• W3041744102 hasConceptScore W3041744102C32470452 @default.
• W3041744102 hasConceptScore W3041744102C40767141 @default.
• W3041744102 hasConceptScore W3041744102C502942594 @default.
• W3041744102 hasConceptScore W3041744102C54355233 @default.
• W3041744102 hasConceptScore W3041744102C71924100 @default.
• W3041744102 hasConceptScore W3041744102C86803240 @default.
• W3041744102 hasConceptScore W3041744102C95444343 @default.
• W3041744102 hasLocation W30417441021 @default.
• W3041744102 hasOpenAccess W3041744102 @default.
• W3041744102 hasPrimaryLocation W30417441021 @default.
• W3041744102 hasRelatedWork W1488704169 @default.
• W3041744102 hasRelatedWork W1913056497 @default.
• W3041744102 hasRelatedWork W1971937190 @default.
• W3041744102 hasRelatedWork W1984733772 @default.
• W3041744102 hasRelatedWork W2004097098 @default.
• W3041744102 hasRelatedWork W2008084061 @default.

• next