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Article: Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish

TitleFunctions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish
Authors
Issue Date2015
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2015, v. 125 n. 19, p. 2974-2984 How to Cite?
AbstractIsocitrate dehydrogenase 1 mutation (IDH1-R132H) was recently identified in acute myeloid leukemia with normal cytogenetics. The mutant enzyme is thought to convert α-ketoglutarate to the pathogenic 2-hydroxyglutarate (2-HG) that affects DNA methylation via inhibition of ten-eleven translocation 2. However, the role of wild-type IDH1 in normal hematopoiesis and its relevance to acute myeloid leukemia is unknown. Here we showed that zebrafish idh1 (zidh1) knockdown by morpholino and targeted mutagenesis by transcription activator–like effector nuclease might induce blockade in myeloid differentiation, as evident by an increase in pu.1 and decrease in mpo, l-plastin, and mpeg1 expression, and significantly reduce definitive hematopoiesis. Morpholino knockdown of zidh2 also induced a blockade in myeloid differentiation but definitive hematopoiesis was not affected. The hematopoietic phenotype of zidh1 knockdown was not rescuable by zidh2 messenger RNA, suggesting nonredundant functions. Overexpression of human IDH1-R132H or its zebrafish ortholog resulted in 2-HG elevation and expansion of myelopoiesis in zebrafish embryos. A human IDH1-R132H–specific inhibitor (AGI-5198) significantly ameliorated both hematopoietic and 2-HG responses in human but not zebrafish IDH1 mutant expression. The results provided important insights to the role of zidh1 in myelopoiesis and definitive hematopoiesis and of IDH1-R132H in leukemogenesis.
Persistent Identifierhttp://hdl.handle.net/10722/211834
ISSN
2017 Impact Factor: 15.132
2015 SCImago Journal Rankings: 6.395
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorShi, X-
dc.contributor.authorHe, B-
dc.contributor.authorMa, CH-
dc.contributor.authorGuo, Y-
dc.contributor.authorChi, Y-
dc.contributor.authorMan, CH-
dc.contributor.authorZhang, W-
dc.contributor.authorZhang, Y-
dc.contributor.authorWen, Z-
dc.contributor.authorCheng, T-
dc.contributor.authorLeung, AYH-
dc.date.accessioned2015-07-21T02:12:37Z-
dc.date.available2015-07-21T02:12:37Z-
dc.date.issued2015-
dc.identifier.citationBlood, 2015, v. 125 n. 19, p. 2974-2984-
dc.identifier.issn0006-4971-
dc.identifier.urihttp://hdl.handle.net/10722/211834-
dc.description.abstractIsocitrate dehydrogenase 1 mutation (IDH1-R132H) was recently identified in acute myeloid leukemia with normal cytogenetics. The mutant enzyme is thought to convert α-ketoglutarate to the pathogenic 2-hydroxyglutarate (2-HG) that affects DNA methylation via inhibition of ten-eleven translocation 2. However, the role of wild-type IDH1 in normal hematopoiesis and its relevance to acute myeloid leukemia is unknown. Here we showed that zebrafish idh1 (zidh1) knockdown by morpholino and targeted mutagenesis by transcription activator–like effector nuclease might induce blockade in myeloid differentiation, as evident by an increase in pu.1 and decrease in mpo, l-plastin, and mpeg1 expression, and significantly reduce definitive hematopoiesis. Morpholino knockdown of zidh2 also induced a blockade in myeloid differentiation but definitive hematopoiesis was not affected. The hematopoietic phenotype of zidh1 knockdown was not rescuable by zidh2 messenger RNA, suggesting nonredundant functions. Overexpression of human IDH1-R132H or its zebrafish ortholog resulted in 2-HG elevation and expansion of myelopoiesis in zebrafish embryos. A human IDH1-R132H–specific inhibitor (AGI-5198) significantly ameliorated both hematopoietic and 2-HG responses in human but not zebrafish IDH1 mutant expression. The results provided important insights to the role of zidh1 in myelopoiesis and definitive hematopoiesis and of IDH1-R132H in leukemogenesis.-
dc.languageeng-
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/-
dc.relation.ispartofBlood-
dc.titleFunctions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish-
dc.typeArticle-
dc.identifier.emailMa, CH: alvinma@hku.hk-
dc.identifier.emailMan, CH: csman729@hku.hk-
dc.identifier.emailLeung, AYH: ayhleung@hku.hk-
dc.identifier.authorityMa, CH=rp01810-
dc.identifier.authorityMan, CH=rp02543-
dc.identifier.authorityLeung, AYH=rp00265-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1182/blood-2014-09-601187-
dc.identifier.pmid25778530-
dc.identifier.scopuseid_2-s2.0-84929175332-
dc.identifier.hkuros245633-
dc.identifier.hkuros276270-
dc.identifier.volume125-
dc.identifier.issue19-
dc.identifier.spage2974-
dc.identifier.epage2984-
dc.identifier.isiWOS:000355687500018-
dc.publisher.placeUnited States-

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