Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia
B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has b...
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| Veröffentlicht in: | Leukemia 2021-05, Vol.35 (5), p.1463-1474 |
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| creator | Schleiss, Cedric Carapito, Raphael Fornecker, Luc-Matthieu Muller, Leslie Paul, Nicodème Tahar, Ouria Pichot, Angelique Tavian, Manuela Nicolae, Alina Miguet, Laurent Mauvieux, Laurent Herbrecht, Raoul Cianferani, Sarah Freund, Jean-Noel Carapito, Christine Maumy-Bertrand, Myriam Bahram, Seiamak Bertrand, Frederic Vallat, Laurent |
| description | B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand–receptor interactions. |
| doi_str_mv | 10.1038/s41375-021-01221-5 |
| format | Article |
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Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand–receptor interactions.</description><identifier>ISSN: 0887-6924</identifier><identifier>EISSN: 1476-5551</identifier><identifier>DOI: 10.1038/s41375-021-01221-5</identifier><identifier>PMID: 33833385</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 14/1 ; 631/67/1990/283/1895 ; 631/67/69 ; 692/420/755 ; 82/58 ; Aged ; B cells ; B-cell lymphoma ; B-cell receptor ; B-Lymphocytes - metabolism ; BCR-ABL protein ; Cancer Research ; Cell proliferation ; Cell Proliferation - genetics ; Cell receptors ; Cellular signal transduction ; Chronic lymphocytic leukemia ; Critical Care Medicine ; Development and progression ; EGR-1 protein ; Female ; Genes ; Genetic aspects ; Health aspects ; Hematology ; Human health and pathology ; Humans ; Immunology ; Intensive ; Internal Medicine ; Leukemia ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Life Sciences ; Lymphatic leukemia ; Lymphocyte Activation - genetics ; Lymphocytes B ; Male ; Mathematical models ; Mathematics ; Medicine ; Medicine & Public Health ; Middle Aged ; Mutation ; NF-κB protein ; Oncology ; Proteins ; Proteome - genetics ; Proteomics ; Proteomics - methods ; Receptors ; Receptors, Antigen, B-Cell - genetics ; Signal Transduction - genetics ; Signaling ; Statistics ; Transcription ; Transcription, Genetic - genetics</subject><ispartof>Leukemia, 2021-05, Vol.35 (5), p.1463-1474</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021. 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Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand–receptor interactions.</description><subject>13/31</subject><subject>14/1</subject><subject>631/67/1990/283/1895</subject><subject>631/67/69</subject><subject>692/420/755</subject><subject>82/58</subject><subject>Aged</subject><subject>B cells</subject><subject>B-cell lymphoma</subject><subject>B-cell receptor</subject><subject>B-Lymphocytes - metabolism</subject><subject>BCR-ABL protein</subject><subject>Cancer Research</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - genetics</subject><subject>Cell receptors</subject><subject>Cellular signal transduction</subject><subject>Chronic lymphocytic leukemia</subject><subject>Critical Care Medicine</subject><subject>Development and progression</subject><subject>EGR-1 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multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia</title><author>Schleiss, Cedric ; Carapito, Raphael ; Fornecker, Luc-Matthieu ; Muller, Leslie ; Paul, Nicodème ; Tahar, Ouria ; Pichot, Angelique ; Tavian, Manuela ; Nicolae, Alina ; Miguet, Laurent ; Mauvieux, Laurent ; Herbrecht, Raoul ; Cianferani, Sarah ; Freund, Jean-Noel ; Carapito, Christine ; Maumy-Bertrand, Myriam ; Bahram, Seiamak ; Bertrand, Frederic ; Vallat, Laurent</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c606t-331b0852b197d4ff1c8028e786ac2abd2d34fd44647663413ae3daa2fa63d9ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/31</topic><topic>14/1</topic><topic>631/67/1990/283/1895</topic><topic>631/67/69</topic><topic>692/420/755</topic><topic>82/58</topic><topic>Aged</topic><topic>B cells</topic><topic>B-cell lymphoma</topic><topic>B-cell 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titles)</collection><jtitle>Leukemia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Schleiss, Cedric</au><au>Carapito, Raphael</au><au>Fornecker, Luc-Matthieu</au><au>Muller, Leslie</au><au>Paul, Nicodème</au><au>Tahar, Ouria</au><au>Pichot, Angelique</au><au>Tavian, Manuela</au><au>Nicolae, Alina</au><au>Miguet, Laurent</au><au>Mauvieux, Laurent</au><au>Herbrecht, Raoul</au><au>Cianferani, Sarah</au><au>Freund, Jean-Noel</au><au>Carapito, Christine</au><au>Maumy-Bertrand, Myriam</au><au>Bahram, Seiamak</au><au>Bertrand, Frederic</au><au>Vallat, Laurent</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia</atitle><jtitle>Leukemia</jtitle><stitle>Leukemia</stitle><addtitle>Leukemia</addtitle><date>2021-05-01</date><risdate>2021</risdate><volume>35</volume><issue>5</issue><spage>1463</spage><epage>1474</epage><pages>1463-1474</pages><issn>0887-6924</issn><eissn>1476-5551</eissn><abstract>B-cell receptor (BCR) signaling is crucial for the pathophysiology of most mature B-cell lymphomas/leukemias and has emerged as a therapeutic target whose effectiveness remains limited by the occurrence of mutations. Therefore, deciphering the cellular program activated downstream this pathway has become of paramount importance for the development of innovative therapies. Using an original ex vivo model of BCR-induced proliferation of chronic lymphocytic leukemia cells, we generated 108 temporal transcriptional and proteomic profiles from 1 h up to 4 days after BCR activation. This dataset revealed a structured temporal response composed of 13,065 transcripts and 4027 proteins, comprising a leukemic proliferative signature consisting of 430 genes and 374 proteins. Mathematical modeling of this complex cellular response further highlighted a transcriptional network driven by 14 early genes linked to proteins involved in cell proliferation. This group includes expected genes (EGR1/2, NF-kB) and genes involved in NF-kB signaling modulation (TANK, ROHF) and immune evasion (KMO, IL4I1) that have not yet been associated with leukemic cells proliferation. Our study unveils the BCR-activated proliferative genetic program in primary leukemic cells. This approach combining temporal measurements with modeling allows identifying new putative targets for innovative therapy of lymphoid malignancies and also cancers dependent on ligand–receptor interactions.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33833385</pmid><doi>10.1038/s41375-021-01221-5</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-0079-319X</orcidid><orcidid>https://orcid.org/0000-0003-4013-4129</orcidid><orcidid>https://orcid.org/0000-0002-5226-7706</orcidid><orcidid>https://orcid.org/0000-0002-4615-1512</orcidid><orcidid>https://orcid.org/0000-0002-6928-9952</orcidid><orcidid>https://orcid.org/0000-0002-0971-3774</orcidid><orcidid>https://orcid.org/0000-0002-0837-8281</orcidid><orcidid>https://orcid.org/0000-0002-7036-442X</orcidid><orcidid>https://orcid.org/0000-0003-3062-2161</orcidid><orcidid>https://orcid.org/0000-0002-9043-1845</orcidid><orcidid>https://orcid.org/0000-0002-1866-971X</orcidid><orcidid>https://orcid.org/0000-0003-2515-5538</orcidid><orcidid>https://orcid.org/0000-0003-4680-3012</orcidid><orcidid>https://orcid.org/0000-0002-9381-4876</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-6924 |
| ispartof | Leukemia, 2021-05, Vol.35 (5), p.1463-1474 |
| issn | 0887-6924 1476-5551 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8102193 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 13/31 14/1 631/67/1990/283/1895 631/67/69 692/420/755 82/58 Aged B cells B-cell lymphoma B-cell receptor B-Lymphocytes - metabolism BCR-ABL protein Cancer Research Cell proliferation Cell Proliferation - genetics Cell receptors Cellular signal transduction Chronic lymphocytic leukemia Critical Care Medicine Development and progression EGR-1 protein Female Genes Genetic aspects Health aspects Hematology Human health and pathology Humans Immunology Intensive Internal Medicine Leukemia Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Life Sciences Lymphatic leukemia Lymphocyte Activation - genetics Lymphocytes B Male Mathematical models Mathematics Medicine Medicine & Public Health Middle Aged Mutation NF-κB protein Oncology Proteins Proteome - genetics Proteomics Proteomics - methods Receptors Receptors, Antigen, B-Cell - genetics Signal Transduction - genetics Signaling Statistics Transcription Transcription, Genetic - genetics |
| title | Temporal multiomic modeling reveals a B-cell receptor proliferative program in chronic lymphocytic leukemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-21T13%3A01%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Temporal%20multiomic%20modeling%20reveals%20a%20B-cell%20receptor%20proliferative%20program%20in%20chronic%20lymphocytic%20leukemia&rft.jtitle=Leukemia&rft.au=Schleiss,%20Cedric&rft.date=2021-05-01&rft.volume=35&rft.issue=5&rft.spage=1463&rft.epage=1474&rft.pages=1463-1474&rft.issn=0887-6924&rft.eissn=1476-5551&rft_id=info:doi/10.1038/s41375-021-01221-5&rft_dat=%3Cgale_pubme%3EA660954848%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2522497796&rft_id=info:pmid/33833385&rft_galeid=A660954848&rfr_iscdi=true |