Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy
Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry...
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| Veröffentlicht in: | Leukemia 2015-03, Vol.29 (3), p.647-659 |
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| creator | Berlin, C Kowalewski, D J Schuster, H Mirza, N Walz, S Handel, M Schmid-Horch, B Salih, H R Kanz, L Rammensee, H-G Stevanović, S Stickel, J S |
| description | Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8
+
T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4
+
T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML. |
| doi_str_mv | 10.1038/leu.2014.233 |
| format | Article |
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+
T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4
+
T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/leu.2014.233</identifier><identifier>PMID: 25092142</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/31 ; 631/250/580 ; 631/67/1059/2325 ; 692/308/575 ; 692/699/1541/1990/283/1897 ; 82/16 ; 82/58 ; 82/80 ; Acute myeloid leukemia ; Amino Acid Sequence ; Antigen (tumor-associated) ; Antigens ; Cancer Research ; Cancer Vaccines - administration & dosage ; Cancer Vaccines - genetics ; Cancer Vaccines - immunology ; Case-Control Studies ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; CD4-Positive T-Lymphocytes - pathology ; CD8 antigen ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; CD8-Positive T-Lymphocytes - pathology ; Cell recognition ; Chromosome mapping ; Critical Care Medicine ; Enzyme-linked immunosorbent assay ; Epitope mapping ; Epitopes, T-Lymphocyte - chemistry ; Epitopes, T-Lymphocyte - genetics ; Epitopes, T-Lymphocyte - immunology ; Gene Expression ; Genetic aspects ; Health aspects ; Hematology ; Histocompatibility antigen HLA ; Histocompatibility antigens ; Histocompatibility Antigens Class I - chemistry ; Histocompatibility Antigens Class I - genetics ; Histocompatibility Antigens Class I - immunology ; Histocompatibility Antigens Class II - chemistry ; Histocompatibility Antigens Class II - genetics ; Histocompatibility Antigens Class II - immunology ; HLA histocompatibility antigens ; Humans ; Immunoprecipitation ; Immunotherapy ; Immunotherapy, Active - methods ; Innovations ; Intensive ; Interferon ; Internal Medicine ; Leukemia ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - immunology ; Leukemia, Myeloid, Acute - pathology ; Leukemia, Myeloid, Acute - therapy ; Leukocytes ; Ligands ; Lymphocytes T ; Mass Spectrometry ; Mass spectroscopy ; Medicine ; Medicine & Public Health ; Methods ; Molecular Sequence Data ; Myeloid leukemia ; Neoplasm Proteins - genetics ; Neoplasm Proteins - immunology ; Oncology ; original-article ; Patient outcomes ; Peptide Mapping ; Peptides ; Peptides - chemistry ; Peptides - genetics ; Peptides - immunology ; Target recognition ; Tumors ; Vaccines ; γ-Interferon</subject><ispartof>Leukemia, 2015-03, Vol.29 (3), p.647-659</ispartof><rights>Macmillan Publishers Limited 2015</rights><rights>COPYRIGHT 2015 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Mar 2015</rights><rights>Macmillan Publishers Limited 2015.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c721t-baf149d196b7ede69600933471da85e21ddec1298e423e0bc2384d4bb2a3d06e3</citedby><cites>FETCH-LOGICAL-c721t-baf149d196b7ede69600933471da85e21ddec1298e423e0bc2384d4bb2a3d06e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/leu.2014.233$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/leu.2014.233$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25092142$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Berlin, C</creatorcontrib><creatorcontrib>Kowalewski, D J</creatorcontrib><creatorcontrib>Schuster, H</creatorcontrib><creatorcontrib>Mirza, N</creatorcontrib><creatorcontrib>Walz, S</creatorcontrib><creatorcontrib>Handel, M</creatorcontrib><creatorcontrib>Schmid-Horch, B</creatorcontrib><creatorcontrib>Salih, H R</creatorcontrib><creatorcontrib>Kanz, L</creatorcontrib><creatorcontrib>Rammensee, H-G</creatorcontrib><creatorcontrib>Stevanović, S</creatorcontrib><creatorcontrib>Stickel, J S</creatorcontrib><title>Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy</title><title>Leukemia</title><addtitle>Leukemia</addtitle><addtitle>Leukemia</addtitle><description>Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8
+
T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4
+
T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.</description><subject>13/1</subject><subject>13/31</subject><subject>631/250/580</subject><subject>631/67/1059/2325</subject><subject>692/308/575</subject><subject>692/699/1541/1990/283/1897</subject><subject>82/16</subject><subject>82/58</subject><subject>82/80</subject><subject>Acute myeloid leukemia</subject><subject>Amino Acid Sequence</subject><subject>Antigen (tumor-associated)</subject><subject>Antigens</subject><subject>Cancer Research</subject><subject>Cancer Vaccines - administration & dosage</subject><subject>Cancer Vaccines - genetics</subject><subject>Cancer Vaccines - immunology</subject><subject>Case-Control Studies</subject><subject>CD4 antigen</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>CD4-Positive T-Lymphocytes - pathology</subject><subject>CD8 antigen</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>CD8-Positive T-Lymphocytes - pathology</subject><subject>Cell recognition</subject><subject>Chromosome mapping</subject><subject>Critical Care Medicine</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Epitope mapping</subject><subject>Epitopes, T-Lymphocyte - chemistry</subject><subject>Epitopes, T-Lymphocyte - genetics</subject><subject>Epitopes, T-Lymphocyte - immunology</subject><subject>Gene Expression</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Hematology</subject><subject>Histocompatibility antigen HLA</subject><subject>Histocompatibility antigens</subject><subject>Histocompatibility Antigens Class I - chemistry</subject><subject>Histocompatibility Antigens Class I - genetics</subject><subject>Histocompatibility Antigens Class I - immunology</subject><subject>Histocompatibility Antigens Class II - chemistry</subject><subject>Histocompatibility Antigens Class II - genetics</subject><subject>Histocompatibility Antigens Class II - immunology</subject><subject>HLA histocompatibility antigens</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Immunotherapy</subject><subject>Immunotherapy, Active - methods</subject><subject>Innovations</subject><subject>Intensive</subject><subject>Interferon</subject><subject>Internal Medicine</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - immunology</subject><subject>Leukemia, Myeloid, Acute - pathology</subject><subject>Leukemia, Myeloid, Acute - therapy</subject><subject>Leukocytes</subject><subject>Ligands</subject><subject>Lymphocytes T</subject><subject>Mass Spectrometry</subject><subject>Mass spectroscopy</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Methods</subject><subject>Molecular Sequence Data</subject><subject>Myeloid leukemia</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - immunology</subject><subject>Oncology</subject><subject>original-article</subject><subject>Patient outcomes</subject><subject>Peptide Mapping</subject><subject>Peptides</subject><subject>Peptides - chemistry</subject><subject>Peptides - genetics</subject><subject>Peptides - immunology</subject><subject>Target recognition</subject><subject>Tumors</subject><subject>Vaccines</subject><subject>γ-Interferon</subject><issn>0887-6924</issn><issn>1476-5551</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkt-L1DAQx4Mo3t7pm88SEOQe7JpfTdt7Ww71hBVf9DmkyXQ3Z9vUJEX2vzdlT13lUMnDQOYz38lMvgg9o2RNCa9f9zCvGaFizTh_gFZUVLIoy5I-RCtS11UhGybO0HmMt4QsSfkYnbGSNIwKtkLzBz1NbtzhtAd8s93g3u30aP0AuM8xGj0B9h3WZk6AhwP03lmce36BwekrrHHSYQcJLM5CwWuzx8l_08HiCabkLBStjjnrhmEefe4S9HR4gh51uo_w9C5eoM9v33y6vim2H9-9v95sC1MxmnJlR0VjaSPbCizIRhLScC4qanVdAqPWgqGsqUEwDqQ1jNfCirZlmlsigV-gy6NuftnXGWJSg4sG-jwa-DkqKivJy7IW5D9QSTmrhBAZffEHeuvnMOZBVP4DKjmtKPkblbWIaGrG2S9qp3tQbux8CtosrdVGkJLKpi6Xjut7qHxs_gXjR-hcvv-t4OVJwR50n_bR93NyfoxqIylh2Tus-hd4qvjqCJrgYwzQqSm4QYeDokQtRlTZFGox4rKEjD-_m35uB7A_4R_Oy0BxBGJOjTsIJ-u5T_A7o-jjhQ</recordid><startdate>20150301</startdate><enddate>20150301</enddate><creator>Berlin, C</creator><creator>Kowalewski, D J</creator><creator>Schuster, H</creator><creator>Mirza, N</creator><creator>Walz, S</creator><creator>Handel, M</creator><creator>Schmid-Horch, B</creator><creator>Salih, H R</creator><creator>Kanz, L</creator><creator>Rammensee, H-G</creator><creator>Stevanović, S</creator><creator>Stickel, J S</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</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>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope></search><sort><creationdate>20150301</creationdate><title>Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy</title><author>Berlin, C ; Kowalewski, D J ; Schuster, H ; Mirza, N ; Walz, S ; Handel, M ; Schmid-Horch, B ; Salih, H R ; Kanz, L ; Rammensee, H-G ; Stevanović, S ; Stickel, J S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c721t-baf149d196b7ede69600933471da85e21ddec1298e423e0bc2384d4bb2a3d06e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13/1</topic><topic>13/31</topic><topic>631/250/580</topic><topic>631/67/1059/2325</topic><topic>692/308/575</topic><topic>692/699/1541/1990/283/1897</topic><topic>82/16</topic><topic>82/58</topic><topic>82/80</topic><topic>Acute myeloid leukemia</topic><topic>Amino Acid Sequence</topic><topic>Antigen (tumor-associated)</topic><topic>Antigens</topic><topic>Cancer Research</topic><topic>Cancer Vaccines - administration & dosage</topic><topic>Cancer Vaccines - genetics</topic><topic>Cancer Vaccines - immunology</topic><topic>Case-Control Studies</topic><topic>CD4 antigen</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>CD4-Positive T-Lymphocytes - pathology</topic><topic>CD8 antigen</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>CD8-Positive T-Lymphocytes - pathology</topic><topic>Cell recognition</topic><topic>Chromosome mapping</topic><topic>Critical Care Medicine</topic><topic>Enzyme-linked immunosorbent assay</topic><topic>Epitope mapping</topic><topic>Epitopes, T-Lymphocyte - chemistry</topic><topic>Epitopes, T-Lymphocyte - genetics</topic><topic>Epitopes, T-Lymphocyte - immunology</topic><topic>Gene Expression</topic><topic>Genetic aspects</topic><topic>Health aspects</topic><topic>Hematology</topic><topic>Histocompatibility antigen HLA</topic><topic>Histocompatibility antigens</topic><topic>Histocompatibility Antigens Class I - 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Academic</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Berlin, C</au><au>Kowalewski, D J</au><au>Schuster, H</au><au>Mirza, N</au><au>Walz, S</au><au>Handel, M</au><au>Schmid-Horch, B</au><au>Salih, H R</au><au>Kanz, L</au><au>Rammensee, H-G</au><au>Stevanović, S</au><au>Stickel, J S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2015-03-01</date><risdate>2015</risdate><volume>29</volume><issue>3</issue><spage>647</spage><epage>659</epage><pages>647-659</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8
+
T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4
+
T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25092142</pmid><doi>10.1038/leu.2014.233</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Leukemia, 2015-03, Vol.29 (3), p.647-659 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1676355840 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | 13/1 13/31 631/250/580 631/67/1059/2325 692/308/575 692/699/1541/1990/283/1897 82/16 82/58 82/80 Acute myeloid leukemia Amino Acid Sequence Antigen (tumor-associated) Antigens Cancer Research Cancer Vaccines - administration & dosage Cancer Vaccines - genetics Cancer Vaccines - immunology Case-Control Studies CD4 antigen CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism CD4-Positive T-Lymphocytes - pathology CD8 antigen CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism CD8-Positive T-Lymphocytes - pathology Cell recognition Chromosome mapping Critical Care Medicine Enzyme-linked immunosorbent assay Epitope mapping Epitopes, T-Lymphocyte - chemistry Epitopes, T-Lymphocyte - genetics Epitopes, T-Lymphocyte - immunology Gene Expression Genetic aspects Health aspects Hematology Histocompatibility antigen HLA Histocompatibility antigens Histocompatibility Antigens Class I - chemistry Histocompatibility Antigens Class I - genetics Histocompatibility Antigens Class I - immunology Histocompatibility Antigens Class II - chemistry Histocompatibility Antigens Class II - genetics Histocompatibility Antigens Class II - immunology HLA histocompatibility antigens Humans Immunoprecipitation Immunotherapy Immunotherapy, Active - methods Innovations Intensive Interferon Internal Medicine Leukemia Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - immunology Leukemia, Myeloid, Acute - pathology Leukemia, Myeloid, Acute - therapy Leukocytes Ligands Lymphocytes T Mass Spectrometry Mass spectroscopy Medicine Medicine & Public Health Methods Molecular Sequence Data Myeloid leukemia Neoplasm Proteins - genetics Neoplasm Proteins - immunology Oncology original-article Patient outcomes Peptide Mapping Peptides Peptides - chemistry Peptides - genetics Peptides - immunology Target recognition Tumors Vaccines γ-Interferon |
| title | Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-12T21%3A37%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Mapping%20the%20HLA%20ligandome%20landscape%20of%20acute%20myeloid%20leukemia:%20a%20targeted%20approach%20toward%20peptide-based%20immunotherapy&rft.jtitle=Leukemia&rft.au=Berlin,%20C&rft.date=2015-03-01&rft.volume=29&rft.issue=3&rft.spage=647&rft.epage=659&rft.pages=647-659&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/leu.2014.233&rft_dat=%3Cgale_proqu%3EA405169854%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1660498232&rft_id=info:pmid/25092142&rft_galeid=A405169854&rfr_iscdi=true |