Shared roles for Scl and Lyl1 in murine platelet production and function

Chiu, SK; Orive, SL; Moon, MJ; Saw, J; Ellis, S; Kile, BT; Huang, Y; Chacon, D; Pimanda, JE; Beck, D; Hamilton, JR; Tremblay, CS; Curtis, DJ

Shared roles for Scl and Lyl1 in murine platelet production and function

Chiu, SK Orive, SL Moon, MJ Saw, J Ellis, S Kile, BT Huang, Y

Chacon, D

Pimanda, JE

Beck, D Hamilton, JR Tremblay, CS Curtis, DJ

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Publication Type:: Journal Article
Citation:: Blood, 2019, 134 (10), pp. 826 - 835
Issue Date:: 2019-09-05

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Field	Value	Language
dc.contributor.author	Chiu, SK	en_US
dc.contributor.author	Orive, SL	en_US
dc.contributor.author	Moon, MJ	en_US
dc.contributor.author	Saw, J	en_US
dc.contributor.author	Ellis, S	en_US
dc.contributor.author	Kile, BT	en_US
dc.contributor.author	Huang, Y https://orcid.org/0000-0002-7003-3110	en_US
dc.contributor.author	Chacon, D https://orcid.org/0000-0003-3729-1385	en_US
dc.contributor.author	Pimanda, JE https://orcid.org/0000-0002-0509-8962	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Hamilton, JR	en_US
dc.contributor.author	Tremblay, CS	en_US
dc.contributor.author	Curtis, DJ	en_US
dc.date.accessioned	2020-03-19T04:27:04Z
dc.date.available	2019-07-11	en_US
dc.date.available	2020-03-19T04:27:04Z
dc.date.issued	2019-09-05	en_US
dc.identifier.citation	Blood, 2019, 134 (10), pp. 826 - 835	en_US
dc.identifier.issn	0006-4971	en_US
dc.identifier.uri	http://hdl.handle.net/10453/139408
dc.description.abstract	© 2019 by The American Society of Hematology. The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, lymphoblastic leukemia 1 (Lyl1) might explain this observation. To determine whether Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking 1 or both factors in megakaryocytes. Conditional Scl knockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4Sclc-KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4Sclc-KO mice generated on an Lyl1-null background (double knockout [DKO] mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation, and markedly impaired platelet aggregation. DKO megakaryocytes, but not single-knockout megakaryocytes, had reduced expression of Gata1, Fli1, Nfe2, and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets, and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production by regulating expression of partner proteins including Gata1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations in inherited thrombocytopenia.	en_US
dc.relation	http://purl.org/au-research/grants/nhmrc/APP1073768
dc.relation.ispartof	Blood	en_US
dc.relation.isbasedon	10.1182/blood.2019896175	en_US
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Blood Platelets	en_US
dc.subject.mesh	Megakaryocytes	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Transgenic	en_US
dc.subject.mesh	Mice, Knockout	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Thrombocytopenia	en_US
dc.subject.mesh	Neoplasm Proteins	en_US
dc.subject.mesh	Thrombopoiesis	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	GATA1 Transcription Factor	en_US
dc.subject.mesh	Basic Helix-Loop-Helix Transcription Factors	en_US
dc.subject.mesh	T-Cell Acute Lymphocytic Leukemia Protein 1	en_US
dc.title	Shared roles for Scl and Lyl1 in murine platelet production and function	en_US
dc.type	Journal Article
utslib.citation.volume	10	en_US
utslib.citation.volume	134	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	1114 Paediatrics and Reproductive Medicine	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Software
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access	*
pubs.issue	10	en_US
pubs.publication-status	Published	en_US
pubs.volume	134	en_US

Abstract:

© 2019 by The American Society of Hematology. The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Scl have not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, lymphoblastic leukemia 1 (Lyl1) might explain this observation. To determine whether Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking 1 or both factors in megakaryocytes. Conditional Scl knockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4Sclc-KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4Sclc-KO mice generated on an Lyl1-null background (double knockout [DKO] mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation, and markedly impaired platelet aggregation. DKO megakaryocytes, but not single-knockout megakaryocytes, had reduced expression of Gata1, Fli1, Nfe2, and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scl and Lyl1 E-box binding sites that were also enriched for Gata1, Ets, and Runx1 motifs. Thus, Scl and Lyl1 share functional roles in platelet production by regulating expression of partner proteins including Gata1. We propose that this functional redundancy provides one explanation for the absence of Scl and Lyl1 mutations in inherited thrombocytopenia.

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http://hdl.handle.net/10453/139408