Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis
The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified...
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| Veröffentlicht in: | The Journal of clinical investigation 2016-03, Vol.126 (3), p.905-920 |
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| creator | Andricovich, Jaclyn Kai, Yan Peng, Weiqun Foudi, Adlen Tzatsos, Alexandros |
| description | The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context. |
| doi_str_mv | 10.1172/JCI84014 |
| format | Article |
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These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI84014</identifier><identifier>PMID: 26808549</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Animals ; Biomedical research ; Bone marrow ; Cancer ; Care and treatment ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Cell Transformation, Neoplastic ; Complications and side effects ; Coronary vessels ; Development and progression ; Endothelium ; Epigenetics ; Experiments ; F-Box Proteins - physiology ; Gene expression ; Gene Expression Regulation, Leukemic ; Genetic aspects ; Hematopoiesis ; Hematopoietic stem cells ; Humans ; Hybridization ; Jumonji Domain-Containing Histone Demethylases - physiology ; Leukemia ; Lymphoma - enzymology ; Lymphoma - pathology ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; Physiological aspects ; Proteins ; Proto-Oncogene Proteins p21(ras) - genetics ; RNA sequencing ; Rodents ; Software ; Survival analysis</subject><ispartof>The Journal of clinical investigation, 2016-03, Vol.126 (3), p.905-920</ispartof><rights>COPYRIGHT 2016 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Mar 2016</rights><rights>Copyright © 2016, American Society for Clinical Investigation 2016 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c637t-704ae674c52727a5aec5668479b4e5072a9ece17158b245c2533e9d3de527e5e3</citedby><cites>FETCH-LOGICAL-c637t-704ae674c52727a5aec5668479b4e5072a9ece17158b245c2533e9d3de527e5e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767361/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767361/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26808549$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Andricovich, Jaclyn</creatorcontrib><creatorcontrib>Kai, Yan</creatorcontrib><creatorcontrib>Peng, Weiqun</creatorcontrib><creatorcontrib>Foudi, Adlen</creatorcontrib><creatorcontrib>Tzatsos, Alexandros</creatorcontrib><title>Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context.</description><subject>Animals</subject><subject>Biomedical research</subject><subject>Bone marrow</subject><subject>Cancer</subject><subject>Care and treatment</subject><subject>Cell Differentiation</subject><subject>Cell Line, Tumor</subject><subject>Cell Lineage</subject><subject>Cell Transformation, Neoplastic</subject><subject>Complications and side effects</subject><subject>Coronary vessels</subject><subject>Development and progression</subject><subject>Endothelium</subject><subject>Epigenetics</subject><subject>Experiments</subject><subject>F-Box Proteins - physiology</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Leukemic</subject><subject>Genetic aspects</subject><subject>Hematopoiesis</subject><subject>Hematopoietic stem cells</subject><subject>Humans</subject><subject>Hybridization</subject><subject>Jumonji Domain-Containing Histone Demethylases - physiology</subject><subject>Leukemia</subject><subject>Lymphoma - enzymology</subject><subject>Lymphoma - pathology</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mutation</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>RNA sequencing</subject><subject>Rodents</subject><subject>Software</subject><subject>Survival analysis</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNktuKFDEQhhtR3HEVfAJpEEQves056ZuFdTzs6MqCpyshZDI1PVnSydhJi_v2ZnB2mZG5WHJRUPnqp6r-qqqnGJ1gLMnrj9OZYgize9UEc64aRai6X00QIrhpJVVH1aOUrlAhGGcPqyMiFFKctZPq57lLOQaoF9BDXl17k6D-9PYzeVMP0I3eZEi1dwFMB7WNfe9yDyHXLtQhDr3xtQmLukTXBVPyK-hNjuvoILn0uHqwND7Bk208rr6_f_dtet5cXH6YTc8uGiuozI1EzICQzHIiiTTcgOVCKCbbOQOOJDEtWMASczUnjFvCKYV2QRdQCoADPa5O_-mux3kPC1saHIzX68H1ZrjW0Ti9_xPcSnfxt2ZSSCpwEXi5FRjirxFS1r1LFrw3AeKYNJZSCMFbye-AirZVFMmN6vP_0Ks4DqFsYiNIFCK03aE640G7sIylRbsR1WfFLskRVqJQzQGqgwBlnuLf0pX0Hn9ygC-v-OzswYJXewWFyfAnd2ZMSc--frk7e_ljn32xw67A-LxK0Y_ZxZD2we1i7RBTGmB56x9GenPl-ubKC_ps1-9b8Oas6V-Z9PJF</recordid><startdate>20160301</startdate><enddate>20160301</enddate><creator>Andricovich, Jaclyn</creator><creator>Kai, Yan</creator><creator>Peng, Weiqun</creator><creator>Foudi, Adlen</creator><creator>Tzatsos, Alexandros</creator><general>American Society for Clinical Investigation</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>7T5</scope><scope>7TM</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20160301</creationdate><title>Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis</title><author>Andricovich, Jaclyn ; Kai, Yan ; Peng, Weiqun ; Foudi, Adlen ; Tzatsos, Alexandros</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c637t-704ae674c52727a5aec5668479b4e5072a9ece17158b245c2533e9d3de527e5e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Biomedical research</topic><topic>Bone marrow</topic><topic>Cancer</topic><topic>Care and treatment</topic><topic>Cell Differentiation</topic><topic>Cell Line, Tumor</topic><topic>Cell Lineage</topic><topic>Cell Transformation, Neoplastic</topic><topic>Complications and side effects</topic><topic>Coronary vessels</topic><topic>Development and progression</topic><topic>Endothelium</topic><topic>Epigenetics</topic><topic>Experiments</topic><topic>F-Box Proteins - physiology</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Leukemic</topic><topic>Genetic aspects</topic><topic>Hematopoiesis</topic><topic>Hematopoietic stem cells</topic><topic>Humans</topic><topic>Hybridization</topic><topic>Jumonji Domain-Containing Histone Demethylases - physiology</topic><topic>Leukemia</topic><topic>Lymphoma - enzymology</topic><topic>Lymphoma - pathology</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mutation</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>RNA sequencing</topic><topic>Rodents</topic><topic>Software</topic><topic>Survival analysis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Andricovich, Jaclyn</creatorcontrib><creatorcontrib>Kai, Yan</creatorcontrib><creatorcontrib>Peng, Weiqun</creatorcontrib><creatorcontrib>Foudi, Adlen</creatorcontrib><creatorcontrib>Tzatsos, Alexandros</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Andricovich, Jaclyn</au><au>Kai, Yan</au><au>Peng, Weiqun</au><au>Foudi, Adlen</au><au>Tzatsos, Alexandros</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2016-03-01</date><risdate>2016</risdate><volume>126</volume><issue>3</issue><spage>905</spage><epage>920</epage><pages>905-920</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Animals Biomedical research Bone marrow Cancer Care and treatment Cell Differentiation Cell Line, Tumor Cell Lineage Cell Transformation, Neoplastic Complications and side effects Coronary vessels Development and progression Endothelium Epigenetics Experiments F-Box Proteins - physiology Gene expression Gene Expression Regulation, Leukemic Genetic aspects Hematopoiesis Hematopoietic stem cells Humans Hybridization Jumonji Domain-Containing Histone Demethylases - physiology Leukemia Lymphoma - enzymology Lymphoma - pathology Mice, Inbred C57BL Mice, Knockout Mutation Physiological aspects Proteins Proto-Oncogene Proteins p21(ras) - genetics RNA sequencing Rodents Software Survival analysis |
| title | Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis |
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