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Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors

Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1...

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Autores principales: Phelan, James D., Saba, Ingrid, Zeng, Hui, Kosan, Christian, Messer, Malynda S., Olsson, H. Andre, Fraszczak, Jennifer, Hildeman, David A., Aronow, Bruce J., Möröy, Tarik, Grimes, H. Leighton
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772063/
https://www.ncbi.nlm.nih.gov/pubmed/24068942
http://dx.doi.org/10.1371/journal.pgen.1003713
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author Phelan, James D.
Saba, Ingrid
Zeng, Hui
Kosan, Christian
Messer, Malynda S.
Olsson, H. Andre
Fraszczak, Jennifer
Hildeman, David A.
Aronow, Bruce J.
Möröy, Tarik
Grimes, H. Leighton
author_facet Phelan, James D.
Saba, Ingrid
Zeng, Hui
Kosan, Christian
Messer, Malynda S.
Olsson, H. Andre
Fraszczak, Jennifer
Hildeman, David A.
Aronow, Bruce J.
Möröy, Tarik
Grimes, H. Leighton
author_sort Phelan, James D.
collection PubMed
description Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T-cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1-activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1(−/−) mice. These defects correlate with an inability of Gfi1(−/−) progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity.
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spelling pubmed-37720632013-09-25 Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors Phelan, James D. Saba, Ingrid Zeng, Hui Kosan, Christian Messer, Malynda S. Olsson, H. Andre Fraszczak, Jennifer Hildeman, David A. Aronow, Bruce J. Möröy, Tarik Grimes, H. Leighton PLoS Genet Research Article Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T-cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1-activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1(−/−) mice. These defects correlate with an inability of Gfi1(−/−) progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity. Public Library of Science 2013-09-12 /pmc/articles/PMC3772063/ /pubmed/24068942 http://dx.doi.org/10.1371/journal.pgen.1003713 Text en © 2013 Phelan et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Phelan, James D.
Saba, Ingrid
Zeng, Hui
Kosan, Christian
Messer, Malynda S.
Olsson, H. Andre
Fraszczak, Jennifer
Hildeman, David A.
Aronow, Bruce J.
Möröy, Tarik
Grimes, H. Leighton
Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
title Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
title_full Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
title_fullStr Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
title_full_unstemmed Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
title_short Growth factor independent-1 Maintains Notch1-Dependent Transcriptional Programming of Lymphoid Precursors
title_sort growth factor independent-1 maintains notch1-dependent transcriptional programming of lymphoid precursors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772063/
https://www.ncbi.nlm.nih.gov/pubmed/24068942
http://dx.doi.org/10.1371/journal.pgen.1003713
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