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Contrary to this expectation, genetically engineered mouse studies show that Idh2R172K and Tet2 loss-of-function produce distinct, even opposite, effects on hematopoietic stem and progenitor cells. Epigenetic and single-cell transcriptomic analyses reveal divergent consequences for key hematopoietic and leukemogenic regulators, with partial disconnection between chromatin accessibility/transcriptional changes and DNA methylation alterations. These findings support genotype-specific therapy optimization.",{"@graph":69,"@context":121},[70,84,104],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/distinct-and-opposite-effects-of-leukemogenic-idh-and-tet2-mutations-in-hematopoietic-stem-and-progenitor-cells/383308/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/distinct-and-opposite-effects-of-leukemogenic-idh-and-tet2-mutations-in-hematopoietic-stem-and-progenitor-cells/383308.png","ImageObject",300,407,{"name":92,"@type":93},"CatatanPagi","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24",true,{"@type":101,"interactionType":102,"userInteractionCount":4},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"Why are IDH1/2 and TET2 mutations expected to act through a common oncogenic mechanism?","Question",{"text":111,"@type":112},"They are recurrent in myeloid neoplasms and are often mutually exclusive, which suggests they may converge on shared oncogenic pathways.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"What did the study find about the effects of Idh2R172K versus Tet2 loss-of-function?",{"text":116,"@type":112},"Instead of matching effects, Idh2R172K and Tet2 loss-of-function produced distinct and even opposite molecular alterations in hematopoietic stem and progenitor cells.",{"name":118,"@type":109,"acceptedAnswer":119},"How did epigenetic and single-cell analyses clarify the molecular divergence?",{"text":120,"@type":112},"They showed divergent expression and activity outcomes for key regulators, with chromatin accessibility and transcriptional deregulation partially disconnected from DNA methylation changes.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},383308,1790255817,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":4,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":128,"read_time":41},962090894170,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","RESEARCH ARTICLE  \nMEDICAL SCIENCES  \n OPEN ACCESS  \nDistinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells  \nJerome Fortina,1,2, Ming-Feng Chianga,1, Cem Meydanb,c,d,3, Jonathan Fooxb,c,3, Parameswaran Ramachandrana,3, Julie Lecaa, Franҫois Lemonniera,e, Wanda Y. Lia,f, Miki S. Gamsg , Takashi Sakamotoa, h, Mandy Chua, Chantal Tobina, Eric Laugesena, Troy M. Robinsoni,j, Annick You-Tena, Daniel J. Butlerb, Thorsten Bergera, Mark D. Mindena, Ross L. Levinei, k, l, Cynthia J. Guidosg, Ari M. Melnickm, Christopher E. Masonb,c,d , and Tak W. Maka,f, n,2  \nContributed by Tak W. Mak; received May 24, 2022; accepted December 12, 2022; reviewed by Timothy J. Ley and Ravindra Majeti  \nMutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms. IDH1 andIDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG) . Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in Idh2R172K cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects ofIDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.  \nIDH | TET2 | myeloid neoplasm | epigenetics  \nMyeloid neoplasms are characterized by the altered proliferation and aberrant differentiation of immature myeloid cells (1). Within this disease spectrum, acute myeloid leukemia (AML) has the worst prognosis, which is heavily influenced by the underlying genetics (1–4) . In many cases, AML emerges from myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) transformation, occasionally preceded by clonal hematopoiesis (CH) (1, 5) .  \nAlterations in epigenetic regulators are found in a large proportion of myeloid neoplasms and AML (6). Among these, missense mutations in the genes encoding isocitrate dehydrogenase-1 and-2 (IDH1 andIDH2) are observed in around 20% of AML and 5 to 10% of MDS and MPN (3, 4, 6, 7). These mutations cause substitutions at arginine 132 (R132) in IDH1, at the equivalent residue (R172) in IDH2, or at R140 in IDH2 (3, 4, 8–11) . Canonically, wild-type IDH1/2 catalyzes the reversible conversion of isocitrate into α-ketoglutarate (α-KG) (8) . Mutant IDH1/2 gains neomorphic enzymatic activity, reducing α-KG to D-2-hydoxyglutarate (D-2-HG) (11, 12), a potent inhibitor of several dioxygenases that normally use α-KG as a cofactor (13, 14). Among those enzymes are the ten-eleven translocation (TET) family of methylcytosine dioxygenases, which hydroxylate 5-methylcytosine (5-mC) bases in the DNA to generate 5-hydroxymethylcytosine (5-hmC) (13, 15) . TET2 is mutated in 15 to 30% of MDS or MPN and 10 to 20% of AML (3, 4, 15–20) . TET2 and IDH1/2 lesions are mutually exclusive and display an overlapping hypermethylated phenotype (3, 4, 13, 21) . In the rare instances where both occur in the same tumor, they are most often in distinct subclones (22, 23). Thus, the oncogenic effect of D-2-HGin hematopoietic cells could be mainly attributable to the inhibition of TET2. However, several observations argue against a simple equivalence ofIDH1/2 and TET2 mutations. First, D-2-HG can alter the activity of multiple α-KG-d","cbCaig534IeKhjMA","https://ap.wps.com/l/cbCaig534IeKhjMA","pdf",9508505,12,"English","# Introduction\n## Epigenetic regulators and recurrent mutations in myeloid neoplasms\n## IDH1/2 and TET2 mechanisms\n# Significance","[{\"question\":\"Why are IDH1/2 and TET2 mutations expected to act through a common oncogenic mechanism?\",\"answer\":\"They are recurrent in myeloid neoplasms and are often mutually exclusive, which suggests they may converge on shared oncogenic pathways.\"},{\"question\":\"What did the study find about the effects of Idh2R172K versus Tet2 loss-of-function?\",\"answer\":\"Instead of matching effects, Idh2R172K and Tet2 loss-of-function produced distinct and even opposite molecular alterations in hematopoietic stem and progenitor cells.\"},{\"question\":\"How did epigenetic and single-cell analyses clarify the molecular divergence?\",\"answer\":\"They showed divergent expression and activity outcomes for key regulators, with chromatin accessibility and transcriptional deregulation partially disconnected from DNA methylation changes.\"}]","Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells | PDF"]