Antileukemic effect of azacitidine, a DNA methyltransferase inhibitor, on cell lines of myeloid leukemia associated with Down syndrome
•Azacitidine (AZA) inhibits proliferation of myeloid leukemia associated with Down syndrome (ML-DS) cell lines established from relapsed cases.•Transient azacitidine (AZA) treatment impairs the next-generation clonogenic potential of ML-DS.•Comprehensive differential gene expression analysis indicat...
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Veröffentlicht in: | Experimental hematology 2024-04, Vol.132, p.104179-104179, Article 104179 |
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creator | Tanaka, Tatsuhiko Kudo, Ko Kanezaki, Rika Yuzawa, Kentaro Toki, Tsutomu Okuse, Ryo Kobayashi, Akie Sato, Tomohiko Kamio, Takuya Terui, Kiminori Ito, Etsuro |
description | •Azacitidine (AZA) inhibits proliferation of myeloid leukemia associated with Down syndrome (ML-DS) cell lines established from relapsed cases.•Transient azacitidine (AZA) treatment impairs the next-generation clonogenic potential of ML-DS.•Comprehensive differential gene expression analysis indicates that AZA induces megakaryocytic differentiation in ML-DS.•AZA induces activation of interferon pathway genes without autocrine stimulation.
Myeloid leukemia associated with Down syndrome (ML-DS) responds well to chemotherapy and has a favorable prognosis, but the clinical outcome of patients with refractory or relapsed ML-DS is dismal. We recently reported a case of relapsed ML-DS with an effective response to a DNA methyltransferase inhibitor, azacitidine (AZA). However, the efficacy of AZA for refractory or relapsed ML-DS remains uncertain. Here, we investigated the effects and mechanism of action of AZA on three ML-DS cell lines derived from relapsed cases. AZA inhibited the proliferation of all examined ML-DS cell lines to the same extent as that of AZA-sensitive acute myeloid leukemia non-Down syndrome cell lines. Transient low-dose AZA treatment exerted durable antileukemic effects on ML-DS cells. The inhibitory effect included cell cycle arrest, apoptosis, and reduction of aldehyde dehydrogenase activity. Comprehensive differential gene expression analysis showed that AZA induced megakaryocytic differentiation in all ML-DS cell lines examined. Furthermore, AZA induced activation of type I interferon-stimulated genes, primarily involved in antiproliferation signaling, without stimulation of the interferon receptor-mediated autocrine system. Activation of the type I interferon pathway by stimulation with interferon-α exerted antiproliferative effects on ML-DS cells, suggesting that AZA exerts its antileukemic effects on ML-DS cells at least partially through the type I interferon pathway. Moreover, the effect of AZA on normal hematopoiesis did not differ significantly between individuals with non-Down syndrome and Down syndrome. In summary, this study suggests that AZA is a potentially effective treatment option for ML-DS disease control, including relapsed cases, and has reduced side effects. |
doi_str_mv | 10.1016/j.exphem.2024.104179 |
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Myeloid leukemia associated with Down syndrome (ML-DS) responds well to chemotherapy and has a favorable prognosis, but the clinical outcome of patients with refractory or relapsed ML-DS is dismal. We recently reported a case of relapsed ML-DS with an effective response to a DNA methyltransferase inhibitor, azacitidine (AZA). However, the efficacy of AZA for refractory or relapsed ML-DS remains uncertain. Here, we investigated the effects and mechanism of action of AZA on three ML-DS cell lines derived from relapsed cases. AZA inhibited the proliferation of all examined ML-DS cell lines to the same extent as that of AZA-sensitive acute myeloid leukemia non-Down syndrome cell lines. Transient low-dose AZA treatment exerted durable antileukemic effects on ML-DS cells. The inhibitory effect included cell cycle arrest, apoptosis, and reduction of aldehyde dehydrogenase activity. Comprehensive differential gene expression analysis showed that AZA induced megakaryocytic differentiation in all ML-DS cell lines examined. Furthermore, AZA induced activation of type I interferon-stimulated genes, primarily involved in antiproliferation signaling, without stimulation of the interferon receptor-mediated autocrine system. Activation of the type I interferon pathway by stimulation with interferon-α exerted antiproliferative effects on ML-DS cells, suggesting that AZA exerts its antileukemic effects on ML-DS cells at least partially through the type I interferon pathway. Moreover, the effect of AZA on normal hematopoiesis did not differ significantly between individuals with non-Down syndrome and Down syndrome. In summary, this study suggests that AZA is a potentially effective treatment option for ML-DS disease control, including relapsed cases, and has reduced side effects.</description><identifier>ISSN: 0301-472X</identifier><identifier>EISSN: 1873-2399</identifier><identifier>DOI: 10.1016/j.exphem.2024.104179</identifier><identifier>PMID: 38342295</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Azacitidine - pharmacology ; Azacitidine - therapeutic use ; Cell Line ; DNA - therapeutic use ; Down Syndrome - complications ; Down Syndrome - drug therapy ; Down Syndrome - genetics ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Humans ; Interferon Type I - therapeutic use ; Leukemia, Myeloid, Acute - complications ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Methyltransferases - therapeutic use</subject><ispartof>Experimental hematology, 2024-04, Vol.132, p.104179-104179, Article 104179</ispartof><rights>2024 ISEH -- Society for Hematology and Stem Cells</rights><rights>Copyright © 2024 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c311t-2e415d8af994559d0fb387819eeeaf2190200534a762a416dcba5f82ace6af803</cites><orcidid>0000-0003-1294-8635 ; 0000-0002-1606-7328 ; 0000-0002-0168-2475 ; 0000-0002-0623-8082</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.exphem.2024.104179$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38342295$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tanaka, Tatsuhiko</creatorcontrib><creatorcontrib>Kudo, Ko</creatorcontrib><creatorcontrib>Kanezaki, Rika</creatorcontrib><creatorcontrib>Yuzawa, Kentaro</creatorcontrib><creatorcontrib>Toki, Tsutomu</creatorcontrib><creatorcontrib>Okuse, Ryo</creatorcontrib><creatorcontrib>Kobayashi, Akie</creatorcontrib><creatorcontrib>Sato, Tomohiko</creatorcontrib><creatorcontrib>Kamio, Takuya</creatorcontrib><creatorcontrib>Terui, Kiminori</creatorcontrib><creatorcontrib>Ito, Etsuro</creatorcontrib><title>Antileukemic effect of azacitidine, a DNA methyltransferase inhibitor, on cell lines of myeloid leukemia associated with Down syndrome</title><title>Experimental hematology</title><addtitle>Exp Hematol</addtitle><description>•Azacitidine (AZA) inhibits proliferation of myeloid leukemia associated with Down syndrome (ML-DS) cell lines established from relapsed cases.•Transient azacitidine (AZA) treatment impairs the next-generation clonogenic potential of ML-DS.•Comprehensive differential gene expression analysis indicates that AZA induces megakaryocytic differentiation in ML-DS.•AZA induces activation of interferon pathway genes without autocrine stimulation.
Myeloid leukemia associated with Down syndrome (ML-DS) responds well to chemotherapy and has a favorable prognosis, but the clinical outcome of patients with refractory or relapsed ML-DS is dismal. We recently reported a case of relapsed ML-DS with an effective response to a DNA methyltransferase inhibitor, azacitidine (AZA). However, the efficacy of AZA for refractory or relapsed ML-DS remains uncertain. Here, we investigated the effects and mechanism of action of AZA on three ML-DS cell lines derived from relapsed cases. AZA inhibited the proliferation of all examined ML-DS cell lines to the same extent as that of AZA-sensitive acute myeloid leukemia non-Down syndrome cell lines. Transient low-dose AZA treatment exerted durable antileukemic effects on ML-DS cells. The inhibitory effect included cell cycle arrest, apoptosis, and reduction of aldehyde dehydrogenase activity. Comprehensive differential gene expression analysis showed that AZA induced megakaryocytic differentiation in all ML-DS cell lines examined. Furthermore, AZA induced activation of type I interferon-stimulated genes, primarily involved in antiproliferation signaling, without stimulation of the interferon receptor-mediated autocrine system. Activation of the type I interferon pathway by stimulation with interferon-α exerted antiproliferative effects on ML-DS cells, suggesting that AZA exerts its antileukemic effects on ML-DS cells at least partially through the type I interferon pathway. Moreover, the effect of AZA on normal hematopoiesis did not differ significantly between individuals with non-Down syndrome and Down syndrome. In summary, this study suggests that AZA is a potentially effective treatment option for ML-DS disease control, including relapsed cases, and has reduced side effects.</description><subject>Azacitidine - pharmacology</subject><subject>Azacitidine - therapeutic use</subject><subject>Cell Line</subject><subject>DNA - therapeutic use</subject><subject>Down Syndrome - complications</subject><subject>Down Syndrome - drug therapy</subject><subject>Down Syndrome - genetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Humans</subject><subject>Interferon Type I - therapeutic use</subject><subject>Leukemia, Myeloid, Acute - complications</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Methyltransferases - therapeutic use</subject><issn>0301-472X</issn><issn>1873-2399</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UcuOEzEQtBCIzS78AUI-ctgJfk1mfEGKdmFBWsEFJG5Wx24rDjPjYDss4QP4bhxN4MippVZVdVcVIS84W3LGV693S_y53-K4FEyoulK804_IgvedbITU-jFZMMl4ozrx9YJc5rxjjLWtZk_JheylEkK3C_J7PZUw4OEbjsFS9B5todFT-AU2lODChNcU6O3HNR2xbI9DSTBljwky0jBtwyaUmK5pnKjFYaBDJeSTwHjEIQZHz9pAIedoAxR09CGULb2NDxPNx8mlOOIz8sTDkPH5eV6RL-_efr5539x_uvtws75vrOS8NAIVb10PXmtVrTjmN7Lveq4REbzgmonqUSroVgIUXzm7gdb3AiyuwPdMXpFXs-4-xe8HzMWMIZ8ehwnjIRuhRatqOFpVqJqhNsWcE3qzT2GEdDScmVMDZmfmBsypATM3UGkvzxcOmxHdP9LfyCvgzQzA6vNHwGSyDThZdCHV8I2L4f8X_gDLCptN</recordid><startdate>202404</startdate><enddate>202404</enddate><creator>Tanaka, Tatsuhiko</creator><creator>Kudo, Ko</creator><creator>Kanezaki, Rika</creator><creator>Yuzawa, Kentaro</creator><creator>Toki, Tsutomu</creator><creator>Okuse, Ryo</creator><creator>Kobayashi, Akie</creator><creator>Sato, Tomohiko</creator><creator>Kamio, Takuya</creator><creator>Terui, Kiminori</creator><creator>Ito, Etsuro</creator><general>Elsevier Inc</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><orcidid>https://orcid.org/0000-0003-1294-8635</orcidid><orcidid>https://orcid.org/0000-0002-1606-7328</orcidid><orcidid>https://orcid.org/0000-0002-0168-2475</orcidid><orcidid>https://orcid.org/0000-0002-0623-8082</orcidid></search><sort><creationdate>202404</creationdate><title>Antileukemic effect of azacitidine, a DNA methyltransferase inhibitor, on cell lines of myeloid leukemia associated with Down syndrome</title><author>Tanaka, Tatsuhiko ; Kudo, Ko ; Kanezaki, Rika ; Yuzawa, Kentaro ; Toki, Tsutomu ; Okuse, Ryo ; Kobayashi, Akie ; Sato, Tomohiko ; Kamio, Takuya ; Terui, Kiminori ; Ito, Etsuro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c311t-2e415d8af994559d0fb387819eeeaf2190200534a762a416dcba5f82ace6af803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Azacitidine - pharmacology</topic><topic>Azacitidine - therapeutic use</topic><topic>Cell Line</topic><topic>DNA - therapeutic use</topic><topic>Down Syndrome - complications</topic><topic>Down Syndrome - drug therapy</topic><topic>Down Syndrome - genetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Enzyme Inhibitors - therapeutic use</topic><topic>Humans</topic><topic>Interferon Type I - therapeutic use</topic><topic>Leukemia, Myeloid, Acute - complications</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>Leukemia, Myeloid, Acute - genetics</topic><topic>Methyltransferases - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tanaka, Tatsuhiko</creatorcontrib><creatorcontrib>Kudo, Ko</creatorcontrib><creatorcontrib>Kanezaki, Rika</creatorcontrib><creatorcontrib>Yuzawa, Kentaro</creatorcontrib><creatorcontrib>Toki, Tsutomu</creatorcontrib><creatorcontrib>Okuse, Ryo</creatorcontrib><creatorcontrib>Kobayashi, Akie</creatorcontrib><creatorcontrib>Sato, Tomohiko</creatorcontrib><creatorcontrib>Kamio, Takuya</creatorcontrib><creatorcontrib>Terui, Kiminori</creatorcontrib><creatorcontrib>Ito, Etsuro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental hematology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tanaka, Tatsuhiko</au><au>Kudo, Ko</au><au>Kanezaki, Rika</au><au>Yuzawa, Kentaro</au><au>Toki, Tsutomu</au><au>Okuse, Ryo</au><au>Kobayashi, Akie</au><au>Sato, Tomohiko</au><au>Kamio, Takuya</au><au>Terui, Kiminori</au><au>Ito, Etsuro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antileukemic effect of azacitidine, a DNA methyltransferase inhibitor, on cell lines of myeloid leukemia associated with Down syndrome</atitle><jtitle>Experimental hematology</jtitle><addtitle>Exp Hematol</addtitle><date>2024-04</date><risdate>2024</risdate><volume>132</volume><spage>104179</spage><epage>104179</epage><pages>104179-104179</pages><artnum>104179</artnum><issn>0301-472X</issn><eissn>1873-2399</eissn><abstract>•Azacitidine (AZA) inhibits proliferation of myeloid leukemia associated with Down syndrome (ML-DS) cell lines established from relapsed cases.•Transient azacitidine (AZA) treatment impairs the next-generation clonogenic potential of ML-DS.•Comprehensive differential gene expression analysis indicates that AZA induces megakaryocytic differentiation in ML-DS.•AZA induces activation of interferon pathway genes without autocrine stimulation.
Myeloid leukemia associated with Down syndrome (ML-DS) responds well to chemotherapy and has a favorable prognosis, but the clinical outcome of patients with refractory or relapsed ML-DS is dismal. We recently reported a case of relapsed ML-DS with an effective response to a DNA methyltransferase inhibitor, azacitidine (AZA). However, the efficacy of AZA for refractory or relapsed ML-DS remains uncertain. Here, we investigated the effects and mechanism of action of AZA on three ML-DS cell lines derived from relapsed cases. AZA inhibited the proliferation of all examined ML-DS cell lines to the same extent as that of AZA-sensitive acute myeloid leukemia non-Down syndrome cell lines. Transient low-dose AZA treatment exerted durable antileukemic effects on ML-DS cells. The inhibitory effect included cell cycle arrest, apoptosis, and reduction of aldehyde dehydrogenase activity. Comprehensive differential gene expression analysis showed that AZA induced megakaryocytic differentiation in all ML-DS cell lines examined. Furthermore, AZA induced activation of type I interferon-stimulated genes, primarily involved in antiproliferation signaling, without stimulation of the interferon receptor-mediated autocrine system. Activation of the type I interferon pathway by stimulation with interferon-α exerted antiproliferative effects on ML-DS cells, suggesting that AZA exerts its antileukemic effects on ML-DS cells at least partially through the type I interferon pathway. Moreover, the effect of AZA on normal hematopoiesis did not differ significantly between individuals with non-Down syndrome and Down syndrome. In summary, this study suggests that AZA is a potentially effective treatment option for ML-DS disease control, including relapsed cases, and has reduced side effects.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>38342295</pmid><doi>10.1016/j.exphem.2024.104179</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0003-1294-8635</orcidid><orcidid>https://orcid.org/0000-0002-1606-7328</orcidid><orcidid>https://orcid.org/0000-0002-0168-2475</orcidid><orcidid>https://orcid.org/0000-0002-0623-8082</orcidid></addata></record> |
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subjects | Azacitidine - pharmacology Azacitidine - therapeutic use Cell Line DNA - therapeutic use Down Syndrome - complications Down Syndrome - drug therapy Down Syndrome - genetics Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Humans Interferon Type I - therapeutic use Leukemia, Myeloid, Acute - complications Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Methyltransferases - therapeutic use |
title | Antileukemic effect of azacitidine, a DNA methyltransferase inhibitor, on cell lines of myeloid leukemia associated with Down syndrome |
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