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Article ; Online: Gemtuzumab ozogamicin for acute myeloid leukemia.

Appelbaum, Frederick R / Bernstein, Irwin D

2017 Volume 130, Issue 22, Page(s) 2373–2376

Abstract: On 1 September 2017, the US Food and Drug Administration (FDA) approved gemtuzumab ozogamicin (GO) for the treatment of adults with newly diagnosed ... ...

Abstract	On 1 September 2017, the US Food and Drug Administration (FDA) approved gemtuzumab ozogamicin (GO) for the treatment of adults with newly diagnosed CD33
MeSH term(s)	Aminoglycosides/administration & dosage ; Aminoglycosides/adverse effects ; Aminoglycosides/therapeutic use ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents, Immunological/administration & dosage ; Antineoplastic Agents, Immunological/adverse effects ; Antineoplastic Agents, Immunological/therapeutic use ; Clinical Trials as Topic ; Gemtuzumab ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Meta-Analysis as Topic ; Sialic Acid Binding Ig-like Lectin 3/analysis
Chemical Substances	Aminoglycosides ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents, Immunological ; Sialic Acid Binding Ig-like Lectin 3 ; Gemtuzumab (93NS566KF7)
Language	English
Publishing date	2017-10-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2017-09-797712
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Article ; Online: Visualizing human ESC-derived hematopoiesis.

Hadland, Brandon K / Bernstein, Irwin D

Blood

2013 Volume 121, Issue 5, Page(s) 717–718

Abstract: In this issue of Blood, Rafii et al present an elegant study of human embryonic stem cell (ESC)–derived hematopoiesis incorporating live imaging at the single-cell level to track hematopoietic lineage potential during the endothelial to hematopoietic ... ...

Abstract	In this issue of Blood, Rafii et al present an elegant study of human embryonic stem cell (ESC)–derived hematopoiesis incorporating live imaging at the single-cell level to track hematopoietic lineage potential during the endothelial to hematopoietic transition.
MeSH term(s)	Cell Differentiation ; Embryonic Stem Cells/metabolism ; Endothelial Cells/metabolism ; Hematopoietic Stem Cells/metabolism ; Humans ; Transduction, Genetic
Language	English
Publishing date	2013-01-30
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2012-12-469932
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Article ; Online: Inaccessible LCG Promoters Act as Safeguards to Restrict T Cell Development to Appropriate Notch Signaling Environments.

Furuyama, Suzanne / Wu, Qian Vicky / Varnum-Finney, Barbara / Sandstrom, Richard / Meuleman, Wouter / Stamatoyannopoulos, John A / Bernstein, Irwin D

Stem cell reports

2021 Volume 16, Issue 4, Page(s) 717–726

Abstract: T cell development is restricted to the thymus and is dependent on high levels of Notch signaling induced within the thymic microenvironment. To understand Notch function in thymic restriction, we investigated the basis for target gene selectivity in ... ...

Abstract	T cell development is restricted to the thymus and is dependent on high levels of Notch signaling induced within the thymic microenvironment. To understand Notch function in thymic restriction, we investigated the basis for target gene selectivity in response to quantitative differences in Notch signal strength, focusing on the chromatin architecture of genes essential for T cell differentiation. We find that high Notch signal strength is required to activate promoters of known targets essential for T cell commitment, including Il2ra, Cd3ε, and Rag1, which feature low CpG content (LCG) and DNA inaccessibility in hematopoietic stem progenitor cells. Our findings suggest that promoter DNA inaccessibility at LCG T lineage genes provides robust protection against stochastic activation in inappropriate Notch signaling contexts, limiting T cell development to the thymus.
MeSH term(s)	Animals ; CpG Islands/genetics ; DNA/metabolism ; Deoxyribonuclease I/metabolism ; Mice, Inbred C57BL ; Promoter Regions, Genetic/genetics ; Receptors, Notch/metabolism ; Signal Transduction ; T-Lymphocytes/metabolism ; Mice
Chemical Substances	Receptors, Notch ; DNA (9007-49-2) ; Deoxyribonuclease I (EC 3.1.21.1)
Language	English
Publishing date	2021-03-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2720528-9
ISSN	2213-6711 ; 2213-6711
ISSN (online)	2213-6711
ISSN	2213-6711
DOI	10.1016/j.stemcr.2021.02.017
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Differentiation latency and dormancy signatures define fetal liver HSCs at single cell resolution.

Ishida, Takashi / Heck, Adam M / Varnum-Finney, Barbara / Dozono, Stacey / Nourigat-McKay, Cynthia / Kraskouskas, Katie / Wellington, Rachel / Waltner, Olivia / Root / Jackson, Dana L / Delaney, Colleen / Rafii, Shahin / Bernstein, Irwin D / Trapnell / Hadland, Brandon

bioRxiv : the preprint server for biology

2023

Abstract: Decoding the gene regulatory mechanisms mediating self-renewal of hematopoietic stem cells (HSCs) during their amplification in the fetal liver (FL) is relevant for advancing therapeutic applications aiming to expand transplantable HSCs, a long-standing ... ...

Abstract	Decoding the gene regulatory mechanisms mediating self-renewal of hematopoietic stem cells (HSCs) during their amplification in the fetal liver (FL) is relevant for advancing therapeutic applications aiming to expand transplantable HSCs, a long-standing challenge. Here, to explore intrinsic and extrinsic regulation of self-renewal in FL-HSCs at the single cell level, we engineered a culture platform designed to recapitulate the FL endothelial niche, which supports the amplification of serially engraftable HSCs ex vivo. Leveraging this platform in combination with single cell index flow cytometry, serial transplantation assays, and single cell RNA-sequencing, we elucidated previously unrecognized heterogeneity in immunophenotypically defined FL-HSCs and demonstrated that differentiation latency and transcriptional signatures of biosynthetic dormancy are distinguishing properties of self-renewing FL-HSCs with capacity for serial, long-term multilineage hematopoietic reconstitution. Altogether, our findings provide key insights into HSC expansion and generate a novel resource for future exploration of the intrinsic and niche-derived signaling pathways that support FL-HSC self-renewal.
Language	English
Publishing date	2023-06-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.01.543314
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Engineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics.

Hadland, Brandon / Varnum-Finney, Barbara / Dozono, Stacey / Dignum, Tessa / Nourigat-McKay, Cynthia / Heck, Adam M / Ishida, Takashi / Jackson, Dana L / Itkin, Tomer / Butler, Jason M / Rafii, Shahin / Trapnell, Cole / Bernstein, Irwin D

Nature communications

2022 Volume 13, Issue 1, Page(s) 1584

Abstract: Hematopoietic stem cells (HSCs) develop from hemogenic endothelium within embryonic arterial vessels such as the aorta of the aorta-gonad-mesonephros region (AGM). To identify the signals responsible for HSC formation, here we use single cell RNA- ... ...

Abstract	Hematopoietic stem cells (HSCs) develop from hemogenic endothelium within embryonic arterial vessels such as the aorta of the aorta-gonad-mesonephros region (AGM). To identify the signals responsible for HSC formation, here we use single cell RNA-sequencing to simultaneously analyze the transcriptional profiles of AGM-derived cells transitioning from hemogenic endothelium to HSCs, and AGM-derived endothelial cells which provide signals sufficient to support HSC maturation and self-renewal. Pseudotemporal ordering reveals dynamics of gene expression during the hemogenic endothelium to HSC transition, identifying surface receptors specifically expressed on developing HSCs. Transcriptional profiling of niche endothelial cells identifies corresponding ligands, including those signaling to Notch receptors, VLA-4 integrin, and CXCR4, which, when integrated in an engineered platform, are sufficient to support the generation of engrafting HSCs. These studies provide a transcriptional map of the signaling interactions necessary for the development of HSCs and advance the goal of engineering HSCs for therapeutic applications.
MeSH term(s)	Gonads ; Hemangioblasts ; Hematopoiesis/genetics ; Hematopoietic Stem Cells/metabolism ; Mesonephros ; Transcriptome
Language	English
Publishing date	2022-03-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-28781-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Engineering stem cell expansion.

Bernstein, Irwin D / Delaney, Colleen

Cell stem cell

2012 Volume 10, Issue 2, Page(s) 113–114

Abstract: In this issue of Cell Stem Cell, Csaszar et al. (2012) develop a culture method that overcomes current limitations in ex vivo hematopoietic stem/progenitor cell expansion by continuously diluting inhibitory signaling factors and maintaining stem cell ... ...

Abstract	In this issue of Cell Stem Cell, Csaszar et al. (2012) develop a culture method that overcomes current limitations in ex vivo hematopoietic stem/progenitor cell expansion by continuously diluting inhibitory signaling factors and maintaining stem cell density. This approach enhances the generation of precursors with potential therapeutic utility.
MeSH term(s)	Animals ; Computer Simulation ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Humans
Language	English
Publishing date	2012-02-03
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2012.01.012
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Article ; Online: NOTCH1 signaling during CD4+ T-cell activation alters transcription factor networks and enhances antigen responsiveness.

Wilkens, Alec B / Fulton, Elena C / Pont, Margot J / Cole, Gabriel O / Leung, Isabel / Stull, Sylvia M / Hart, Matthew R / Bernstein, Irwin D / Furlan, Scott N / Riddell, Stanley R

Blood

2022 Volume 140, Issue 21, Page(s) 2261–2275

Abstract: Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell ... ...

Abstract	Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) effectively treats refractory hematologic malignancies in a subset of patients but can be limited by poor T-cell expansion and persistence in vivo. Less differentiated T-cell states correlate with the capacity of CAR-T to proliferate and mediate antitumor responses, and interventions that limit tumor-specific T-cell differentiation during ex vivo manufacturing enhance efficacy. NOTCH signaling is involved in fate decisions across diverse cell lineages and in memory CD8+ T cells was reported to upregulate the transcription factor FOXM1, attenuate differentiation, and enhance proliferation and antitumor efficacy in vivo. Here, we used a cell-free culture system to provide an agonistic NOTCH1 signal during naïve CD4+ T-cell activation and CAR-T production and studied the effects on differentiation, transcription factor expression, cytokine production, and responses to tumor. NOTCH1 agonism efficiently induced a stem cell memory phenotype in CAR-T derived from naïve but not memory CD4+ T cells and upregulated expression of AhR and c-MAF, driving heightened production of interleukin-22, interleukin-10, and granzyme B. NOTCH1-agonized CD4+ CAR-T demonstrated enhanced antigen responsiveness and proliferated to strikingly higher frequencies in mice bearing human lymphoma xenografts. NOTCH1-agonized CD4+ CAR-T also provided superior help to cotransferred CD8+ CAR-T, driving improved expansion and curative antitumor responses in vivo at low CAR-T doses. Our data expand the mechanisms by which NOTCH can shape CD4+ T-cell behavior and demonstrate that activating NOTCH1 signaling during genetic modification ex vivo is a potential strategy for enhancing the function of T cells engineered with tumor-targeting receptors.
MeSH term(s)	Humans ; Mice ; Animals ; Receptors, Chimeric Antigen ; Immunotherapy, Adoptive ; CD4-Positive T-Lymphocytes ; Transcription Factors ; Lymphoma/drug therapy ; Receptors, Antigen, T-Cell ; Receptor, Notch1/genetics
Chemical Substances	Receptors, Chimeric Antigen ; Transcription Factors ; Receptors, Antigen, T-Cell ; NOTCH1 protein, human ; Receptor, Notch1
Language	English
Publishing date	2022-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021015144
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Article ; Online: Engineering a niche supporting hematopoietic stem cell development using integrated single-cell transcriptomics

Brandon Hadland / Barbara Varnum-Finney / Stacey Dozono / Tessa Dignum / Cynthia Nourigat-McKay / Adam M. Heck / Takashi Ishida / Dana L. Jackson / Tomer Itkin / Jason M. Butler / Shahin Rafii / Cole Trapnell / Irwin D. Bernstein

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 17

Abstract: Here, the authors use single cell RNA-sequencing to generate an atlas of signaling interactions regulating embryonic hematopoietic stem cell (HSC) development and apply this knowledge to engineer a niche sufficient to support HSC maturation in vitro. ...

Abstract	Here, the authors use single cell RNA-sequencing to generate an atlas of signaling interactions regulating embryonic hematopoietic stem cell (HSC) development and apply this knowledge to engineer a niche sufficient to support HSC maturation in vitro.
Keywords	Science ; Q
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Clonal Analysis of Embryonic Hematopoietic Stem Cell Precursors Using Single Cell Index Sorting Combined with Endothelial Cell Niche Co-culture.

Hadland, Brandon K / Varnum-Finney, Barbara / Nourigat-Mckay, Cynthia / Flowers, David / Bernstein, Irwin D

Journal of visualized experiments : JoVE

2018 , Issue 135

Abstract: The ability to study hematopoietic stem cell (HSC) genesis during embryonic development has been limited by the rarity of HSC precursors in the early embryo and the lack of assays that functionally identify the long-term multilineage engraftment ... ...

Abstract	The ability to study hematopoietic stem cell (HSC) genesis during embryonic development has been limited by the rarity of HSC precursors in the early embryo and the lack of assays that functionally identify the long-term multilineage engraftment potential of individual putative HSC precursors. Here, we describe methodology that enables the isolation and characterization of functionally validated HSC precursors at the single cell level. First, we utilize index sorting to catalog the precise phenotypic parameter of each individually sorted cell, using a combination of phenotypic markers to enrich for HSC precursors with additional markers for experimental analysis. Second, each index-sorted cell is co-cultured with vascular niche stroma from the aorta-gonad-mesonephros (AGM) region, which supports the maturation of non-engrafting HSC precursors to functional HSC with multilineage, long-term engraftment potential in transplantation assays. This methodology enables correlation of phenotypic properties of clonal hemogenic precursors with their functional engraftment potential or other properties such as transcriptional profile, providing a means for the detailed analysis of HSC precursor development at the single cell level.
MeSH term(s)	Cell Separation ; Cells, Cultured ; Coculture Techniques/methods ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Female ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Humans ; Pregnancy
Language	English
Publishing date	2018-05-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Video-Audio Media
ISSN	1940-087X
ISSN (online)	1940-087X
DOI	10.3791/56973
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Article: Engineering Stem Cell Expansion

Bernstein, Irwin D / Delaney, Colleen

Cell stem cell. 2012 Feb. 3, v. 10, no. 2

2012

Abstract	In this issue of Cell Stem Cell, Csaszar et al. (2012) develop a culture method that overcomes current limitations in ex vivo hematopoietic stem/progenitor cell expansion by continuously diluting inhibitory signaling factors and maintaining stem cell density. This approach enhances the generation of precursors with potential therapeutic utility.
Keywords	cell culture ; hematopoiesis ; stem cells
Language	English
Dates of publication	2012-0203
Size	p. 113-114.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2375354-7
ISSN	1934-5909
ISSN	1934-5909
DOI	10.1016/j.stem.2012.01.012
Database	NAL-Catalogue (AGRICOLA)

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