The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML
A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental mole...
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| Veröffentlicht in: | The Journal of experimental medicine 2013-01, Vol.210 (1), p.15-22 |
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| creator | Heidel, Florian H Bullinger, Lars Arreba-Tutusaus, Patricia Wang, Zhu Gaebel, Julia Hirt, Carsten Niederwieser, Dietger Lane, Steven W Döhner, Konstanze Vasioukhin, Valera Fischer, Thomas Armstrong, Scott A |
| description | A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1(-/-) HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML. |
| doi_str_mv | 10.1084/jem.20120596 |
| format | Article |
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Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1(-/-) HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20120596</identifier><identifier>PMID: 23277453</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Animals ; Brief Definitive Report ; Cytoskeletal Proteins - genetics ; Cytoskeletal Proteins - metabolism ; Early Growth Response Protein 1 - genetics ; Early Growth Response Protein 1 - metabolism ; Gene Expression Regulation, Leukemic ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells - cytology ; Hematopoietic Stem Cells - metabolism ; Humans ; Kruppel-Like Transcription Factors - genetics ; Kruppel-Like Transcription Factors - metabolism ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Leukemia, Myeloid, Acute - pathology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Prognosis</subject><ispartof>The Journal of experimental medicine, 2013-01, Vol.210 (1), p.15-22</ispartof><rights>2013 Heidel et al. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-dec7fb22c5b54f9015eef911a2b9ffdf6beebe786d295f6025955307dee552c73</citedby><cites>FETCH-LOGICAL-c483t-dec7fb22c5b54f9015eef911a2b9ffdf6beebe786d295f6025955307dee552c73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27923,27924</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23277453$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Heidel, Florian H</creatorcontrib><creatorcontrib>Bullinger, Lars</creatorcontrib><creatorcontrib>Arreba-Tutusaus, Patricia</creatorcontrib><creatorcontrib>Wang, Zhu</creatorcontrib><creatorcontrib>Gaebel, Julia</creatorcontrib><creatorcontrib>Hirt, Carsten</creatorcontrib><creatorcontrib>Niederwieser, Dietger</creatorcontrib><creatorcontrib>Lane, Steven W</creatorcontrib><creatorcontrib>Döhner, Konstanze</creatorcontrib><creatorcontrib>Vasioukhin, Valera</creatorcontrib><creatorcontrib>Fischer, Thomas</creatorcontrib><creatorcontrib>Armstrong, Scott A</creatorcontrib><title>The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>A unique characteristic of hematopoietic stem cells (HSCs) is the ability to self-renew. Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1(-/-) HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. Decreased Llgl1 expression in human acute myeloid leukemia (AML) cells is associated with inferior patient survival. Thus, inactivation of Llgl1 enhances HSC self-renewal and fitness and is associated with unfavorable outcome in human AML.</description><subject>Animals</subject><subject>Brief Definitive Report</subject><subject>Cytoskeletal Proteins - genetics</subject><subject>Cytoskeletal Proteins - metabolism</subject><subject>Early Growth Response Protein 1 - genetics</subject><subject>Early Growth Response Protein 1 - metabolism</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Hematopoietic Stem Cell Transplantation</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Humans</subject><subject>Kruppel-Like Transcription Factors - genetics</subject><subject>Kruppel-Like Transcription Factors - metabolism</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Mutant Strains</subject><subject>Prognosis</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkT1PwzAQhi0EgvKxMSOPDKT46-J4QaoqvkQRA2W2nOTcBiVOiVMk_j1B0Aomphvu0av37iHklLMxZ5m6fMVmLBgXDEy6Q0YcFEsMyGyXjBgTIuGM6QNyGOMrY1wpSPfJgZBCawVyRB7mS6QF1jX1rkdaYo9dUwUXejqrFzWnVfD1GkOBkd49T6mv-oAxUhdKuuraRWhjFQeITh5nx2TPuzriyc88Ii831_PpXTJ7ur2fTmZJoTLZJyUW2udCFJCD8oZxQPSGcydy433p0xwxR52lpTDgUybAAEimS0QAUWh5RK6-c1frvMGywNB3rrarrmpc92FbV9m_m1At7aJ9txKU0VwOAec_AV37tsbY26aKX09wAdt1tByAp0pkmf4fFVoCKKHNgF58o0XXxtih3zbizH6psoMqu1E14Ge_r9jCGzfyE9_Qj2w</recordid><startdate>20130114</startdate><enddate>20130114</enddate><creator>Heidel, Florian H</creator><creator>Bullinger, Lars</creator><creator>Arreba-Tutusaus, Patricia</creator><creator>Wang, Zhu</creator><creator>Gaebel, Julia</creator><creator>Hirt, Carsten</creator><creator>Niederwieser, Dietger</creator><creator>Lane, Steven W</creator><creator>Döhner, Konstanze</creator><creator>Vasioukhin, Valera</creator><creator>Fischer, Thomas</creator><creator>Armstrong, Scott A</creator><general>The Rockefeller University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20130114</creationdate><title>The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML</title><author>Heidel, Florian H ; 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Several genes and signaling pathways control the fine balance between self-renewal and differentiation in HSCs and potentially also in leukemia stem cells. Recently, studies have shed light on developmental molecules and evolutionarily conserved signals as regulators of stem cells in hematopoiesis and leukemia. In this study, we provide evidence that the cell fate determinant Llgl1 (lethal giant larvae homolog 1) plays an important role in regulation of HSCs. Loss of Llgl1 leads to an increase in HSC numbers that show increased repopulation capacity and competitive advantage after transplantation. This advantage increases upon serial transplantation or when stress is applied to HSCs. Llgl1(-/-) HSCs show increased cycling but neither exhaust nor induce leukemia in recipient mice. Llgl1 inactivation is associated with transcriptional repression of transcription factors such as KLF4 (Krüppel-like factor 4) and EGR1 (early-growth-response 1) that are known inhibitors of HSC self-renewal. 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| subjects | Animals Brief Definitive Report Cytoskeletal Proteins - genetics Cytoskeletal Proteins - metabolism Early Growth Response Protein 1 - genetics Early Growth Response Protein 1 - metabolism Gene Expression Regulation, Leukemic Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - metabolism Humans Kruppel-Like Transcription Factors - genetics Kruppel-Like Transcription Factors - metabolism Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Mice Mice, Inbred C57BL Mice, Mutant Strains Prognosis |
| title | The cell fate determinant Llgl1 influences HSC fitness and prognosis in AML |
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