{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T08:54:24Z","timestamp":1771059264474,"version":"3.50.1"},"reference-count":55,"publisher":"American Society of Hematology","issue":"22","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>A large amount of circumstantial evidence has accumulated suggesting that Toll-like receptor (TLR) signals are involved in driving chronic lymphocytic leukemia (CLL) cell proliferation, but direct in\u00a0vivo evidence for this is still lacking. We have now further addressed this possibility by pharmacologically inhibiting or genetically inactivating the TLR pathway in murine CLL and human Richter syndrome (RS) patient-derived xenograft (PDX) cells. Surprisingly, we show that pharmacologic inhibition of TLR signaling by treatment with an IRAK1\/4 inhibitor delays the growth of the transplanted malignant cells in recipient mice, but genetic inactivation of the same pathway by CRISPR\/Cas9-mediated disruption of IRAK4 or its proximal adaptor MyD88 has no effect. We further show that treatment with the IRAK1\/4 inhibitor results in depletion of macrophages and demonstrate that these cells can support the survival and enhance the proliferation of both murine E\u03bc-TCL1 leukemia and human RS cells. We also show that genetic disruption of the B-cell receptor (BCR) by CRISPR\/Cas9 editing of the immunoglobulin M constant region gene inhibits the growth of human RS-PDX cells in\u00a0vivo, consistent with our previous finding with murine E\u03bc-TCL1 leukemia cells. Finally, we show that genetic disruption of IRAK4 does not result in negative selection of human CLL cell lines xenografted in immunodeficient mice. The obtained data suggest that TLR signals are unlikely to represent a major driver of CLL\/RS cell proliferation and provide further evidence that signals from macrophages and the BCR promote the growth and survival of CLL and RS cells in\u00a0vivo.<\/jats:p>","DOI":"10.1182\/blood.2022016272","type":"journal-article","created":{"date-parts":[[2022,9,9]],"date-time":"2022-09-09T21:03:57Z","timestamp":1662757437000},"page":"2335-2347","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":24,"title":["Macrophage- and BCR-derived but not TLR-derived signals support the growth of CLL and Richter syndrome murine models in\u00a0vivo"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7136-7174","authenticated-orcid":false,"given":"Claudio","family":"Martines","sequence":"first","affiliation":[{"name":"1Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Supriya","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"1Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marija","family":"Vujovikj","sequence":"additional","affiliation":[{"name":"2Research Center for Genetic Engineering and Biotechnology, Macedonian Academy of Sciences and Arts, Skopje, North Macedonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Gobessi","sequence":"additional","affiliation":[{"name":"1Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiziana","family":"Vaisitti","sequence":"additional","affiliation":[{"name":"3Functional Genomics Unit, Department of Medical Sciences, University of Turin, Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0632-5036","authenticated-orcid":false,"given":"Silvia","family":"Deaglio","sequence":"additional","affiliation":[{"name":"3Functional Genomics Unit, Department of Medical Sciences, University of Turin, Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8327-1396","authenticated-orcid":false,"given":"Luca","family":"Laurenti","sequence":"additional","affiliation":[{"name":"4Department of Hematology, Catholic University of the Sacred Heart, Gemelli University Hospital, Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandar J.","family":"Dimovski","sequence":"additional","affiliation":[{"name":"2Research Center for Genetic Engineering and Biotechnology, Macedonian Academy of Sciences and Arts, Skopje, North Macedonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9081-5462","authenticated-orcid":false,"given":"Dimitar G.","family":"Efremov","sequence":"additional","affiliation":[{"name":"1Molecular Hematology Unit, International Center for Genetic Engineering and Biotechnology, Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"issue":"2","key":"2022120116265685900_bib1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/cr.2012.152","article-title":"Chronic lymphocytic leukemia: a tale of one or two signals?","volume":"23","author":"Chiorazzi","year":"2013","journal-title":"Cell Res"},{"issue":"10","key":"2022120116265685900_bib2","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1182\/blood.2020010029","article-title":"Exploring the pathways to chronic lymphocytic leukemia","volume":"138","author":"Stevenson","year":"2021  9","journal-title":"Blood"},{"issue":"7415","key":"2022120116265685900_bib3","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nature11309","article-title":"Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling","volume":"489","author":"D\u00fchren-von Minden","year":"2012","journal-title":"Nature"},{"issue":"10","key":"2022120116265685900_bib4","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1182\/blood-2014-07-587790","article-title":"Two types of BCR interactions are positively selected during leukemia development in the E\u03bc-TCL1 transgenic mouse model of CLL","volume":"125","author":"Iacovelli","year":"2015","journal-title":"Blood"},{"key":"2022120116265685900_bib5","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/1479-5876-7-76","article-title":"Intrinsic and extrinsic factors influencing the clinical course of B-cell chronic lymphocytic leukemia: prognostic markers with pathogenetic relevance","volume":"7","author":"Dal-Bo","year":"2009","journal-title":"J\u00a0Transl Med"},{"issue":"3","key":"2022120116265685900_bib6","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.bbamcr.2015.07.009","article-title":"Microenvironment interactions and B-cell receptor signaling in chronic lymphocytic leukemia: implications for disease pathogenesis and treatment","volume":"1863","author":"Ten Hacken","year":"2016","journal-title":"Biochim Biophys Acta"},{"issue":"1","key":"2022120116265685900_bib7","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41598-018-36853-8","article-title":"BCR-associated factors driving chronic lymphocytic leukemia cells proliferation ex\u00a0vivo","volume":"9","author":"Schleiss","year":"2019","journal-title":"Sci Rep"},{"key":"2022120116265685900_bib8","doi-asserted-by":"crossref","first-page":"592205","DOI":"10.3389\/fonc.2020.592205","article-title":"Proliferative signals in chronic lymphocytic leukemia; what are we missing?","volume":"10","author":"Haselager","year":"2020","journal-title":"Front Oncol"},{"issue":"12","key":"2022120116265685900_bib9","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1182\/blood.2020008276","article-title":"B-cell receptor signaling and genetic lesions in TP53 and CDKN2A\/CDKN2B cooperate in Richter transformation","volume":"138","author":"Chakraborty","year":"2021","journal-title":"Blood"},{"issue":"1","key":"2022120116265685900_bib10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1006\/cimm.1998.1360","article-title":"Direct cellular interaction with activated CD4(+) T cells overcomes hyporesponsiveness of B-cell chronic lymphocytic leukemia in\u00a0vitro","volume":"189","author":"Tretter","year":"1998","journal-title":"Cell Immunol"},{"issue":"3","key":"2022120116265685900_bib11","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.celrep.2013.07.011","article-title":"Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells","volume":"4","author":"Os","year":"2013","journal-title":"Cell Rep"},{"key":"2022120116265685900_bib12","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1182\/blood-2012-11-467670","article-title":"IL-21 and CD40L signals from autologous T cells can induce antigen-independent proliferation of CLL cells","volume":"122","author":"Pascutti","year":"2013","journal-title":"Blood"},{"issue":"5","key":"2022120116265685900_bib13","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1016\/S0301-472X(00)00144-2","article-title":"Immunostimulatory CpG-oligonucleotides induce functional high affinity IL-2 receptors on B-CLL cells: costimulation with IL-2 results in a highly immunogenic phenotype","volume":"28","author":"Decker","year":"2000","journal-title":"Exp Hematol"},{"issue":"1","key":"2022120116265685900_bib14","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1182\/blood-2002-01-0189","article-title":"Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin","volume":"101","author":"Decker","year":"2003","journal-title":"Blood"},{"issue":"9","key":"2022120116265685900_bib15","doi-asserted-by":"crossref","first-page":"3152","DOI":"10.1182\/blood-2006-02-005322","article-title":"Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: a study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression","volume":"108","author":"Dicker","year":"2006","journal-title":"Blood"},{"issue":"4","key":"2022120116265685900_bib16","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1182\/blood-2015-05-646935","article-title":"Integration of innate into adaptive immune responses in ZAP-70-positive chronic lymphocytic leukemia","volume":"127","author":"Wagner","year":"2016","journal-title":"Blood"},{"issue":"5","key":"2022120116265685900_bib17","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1002\/1521-4141(200205)32:5<1403::AID-IMMU1403>3.0.CO;2-Y","article-title":"Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22","volume":"32","author":"Ghia","year":"2002","journal-title":"Eur J Immunol"},{"issue":"10","key":"2022120116265685900_bib18","doi-asserted-by":"crossref","first-page":"e109533","DOI":"10.1371\/journal.pone.0109533","article-title":"The gene expression response of chronic lymphocytic leukemia cells to IL-4 is specific, depends on ZAP-70 status and is differentially affected by an NF\u03baB inhibitor","volume":"9","author":"Ruiz-Lafuente","year":"2014","journal-title":"PLoS One"},{"issue":"24","key":"2022120116265685900_bib19","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1182\/blood-2015-11-682906","article-title":"IL-4 enhances expression and function of surface IgM in CLL cells","volume":"127","author":"Aguilar-Hernandez","year":"2016","journal-title":"Blood"},{"issue":"20","key":"2022120116265685900_bib20","doi-asserted-by":"crossref","first-page":"5463","DOI":"10.1182\/blood-2010-12-324210","article-title":"A\u00a0novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease","volume":"117","author":"Bagnara","year":"2011","journal-title":"Blood"},{"key":"2022120116265685900_bib21","doi-asserted-by":"crossref","first-page":"627020","DOI":"10.3389\/fimmu.2021.627020","article-title":"A\u00a0detailed analysis of parameters supporting the engraftment and growth of chronic lymphocytic leukemia cells in immune-deficient mice","volume":"12","author":"Patten","year":"2021","journal-title":"Front Immunol"},{"issue":"2","key":"2022120116265685900_bib22","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1182\/blood-2010-05-284984","article-title":"The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia","volume":"117","author":"Herishanu","year":"2011","journal-title":"Blood"},{"issue":"2","key":"2022120116265685900_bib23","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1158\/0008-5472.CAN-18-0781","article-title":"TLR\u00a0signaling is activated in lymph node-resident CLL cells and is only partially inhibited by ibrutinib","volume":"79","author":"Dadashian","year":"2019","journal-title":"Cancer Res"},{"issue":"1","key":"2022120116265685900_bib24","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/sj.leu.2404417","article-title":"The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease","volume":"21","author":"Longo","year":"2007","journal-title":"Leukemia"},{"issue":"9","key":"2022120116265685900_bib25","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/j.leukres.2009.12.020","article-title":"The proliferative response to CpG-ODN stimulation predicts PFS, TTT and OS in patients with chronic lymphocytic leukemia","volume":"34","author":"Tarnani","year":"2010","journal-title":"Leuk Res"},{"issue":"7","key":"2022120116265685900_bib26","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1182\/blood-2007-11-125450","article-title":"A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies","volume":"111","author":"Lanemo Myhrinder","year":"2008","journal-title":"Blood"},{"issue":"11-12","key":"2022120116265685900_bib27","doi-asserted-by":"crossref","first-page":"665","DOI":"10.2119\/2008-00102.Catera","article-title":"Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation","volume":"14","author":"Catera","year":"2008","journal-title":"Mol Med"},{"issue":"1","key":"2022120116265685900_bib28","doi-asserted-by":"crossref","first-page":"371","DOI":"10.2741\/4108","article-title":"TLR9 signaling defines distinct prognostic subsets in CLL","volume":"18","author":"Efremov","year":"2013","journal-title":"Front Biosci (Landmark Ed)"},{"issue":"3","key":"2022120116265685900_bib29","doi-asserted-by":"crossref","first-page":"901","DOI":"10.4049\/jimmunol.1403189","article-title":"TLR-9 and IL-15 synergy promotes the in vitro clonal expansion of chronic lymphocytic leukemia B cells","volume":"195","author":"Mongini","year":"2015","journal-title":"J\u00a0Immunol"},{"issue":"22","key":"2022120116265685900_bib30","doi-asserted-by":"crossref","first-page":"3064","DOI":"10.1182\/blood.2020005964","article-title":"TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target","volume":"137","author":"Kennedy","year":"2021","journal-title":"Blood"},{"issue":"7332","key":"2022120116265685900_bib31","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nature09671","article-title":"Oncogenically active MYD88 mutations in human lymphoma","volume":"470","author":"Ngo","year":"2011","journal-title":"Nature"},{"issue":"13","key":"2022120116265685900_bib32","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1084\/jem.20151074","article-title":"Selective interleukin-1 receptor-associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy","volume":"212","author":"Kelly","year":"2015","journal-title":"J\u00a0Exp Med"},{"issue":"7","key":"2022120116265685900_bib33","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1182\/blood-2012-12-475111","article-title":"A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstr\u00f6m macroglobulinemia","volume":"122","author":"Yang","year":"2013","journal-title":"Blood"},{"issue":"3","key":"2022120116265685900_bib34","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/bjh.16386","article-title":"Interleukin-1 receptor-associated kinase 4 inhibitor interrupts toll-like receptor signalling and sensitizes chronic lymphocytic leukaemia cells to apoptosis","volume":"189","author":"Delvecchio","year":"2020","journal-title":"Br J Haematol"},{"issue":"1","key":"2022120116265685900_bib35","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s41375-019-0507-8","article-title":"Targeting IRAK4 disrupts inflammatory pathways and delays tumor development in chronic lymphocytic leukemia","volume":"34","author":"Gim\u00e9nez","year":"2020","journal-title":"Leukemia"},{"issue":"12","key":"2022120116265685900_bib36","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1038\/leu.2017.129","article-title":"Targeting antigen-independent proliferation in chronic lymphocytic leukemia through differential kinase inhibition","volume":"31","author":"Slinger","year":"2017","journal-title":"Leukemia"},{"issue":"4","key":"2022120116265685900_bib37","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/s41375-018-0335-2","article-title":"Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment","volume":"33","author":"Gounari","year":"2019","journal-title":"Leukemia"},{"issue":"24","key":"2022120116265685900_bib38","doi-asserted-by":"crossref","first-page":"6408","DOI":"10.1158\/1078-0432.CCR-17-3265","article-title":"Targeting myddosome signaling in Waldenstrom's macroglobulinemia with the interleukin-1 receptor-associated kinase 1\/4 inhibitor R191","volume":"24","author":"Ni","year":"2018","journal-title":"Clin Cancer Res"},{"issue":"13","key":"2022120116265685900_bib39","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1158\/0008-5472.CAN-17-4004","article-title":"Novel Richter syndrome xenograft models to study genetic architecture, biology, and therapy responses","volume":"78","author":"Vaisitti","year":"2018","journal-title":"Cancer Res"},{"issue":"24","key":"2022120116265685900_bib40","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1182\/blood.2020008404","article-title":"ROR1 targeting with the antibody-drug conjugate VLS-101 is effective in Richter syndrome patient-derived xenograft mouse models","volume":"137","author":"Vaisitti","year":"2021","journal-title":"Blood"},{"issue":"10","key":"2022120116265685900_bib41","doi-asserted-by":"crossref","first-page":"3715","DOI":"10.1182\/blood-2007-05-090142","article-title":"Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival","volume":"110","author":"Mancao","year":"2007","journal-title":"Blood"},{"issue":"5","key":"2022120116265685900_bib42","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1002\/eji.201646641","article-title":"Deficiency in IRAK4 activity attenuates manifestations of murine lupus","volume":"47","author":"Murphy","year":"2017","journal-title":"Eur J Immunol"},{"issue":"5","key":"2022120116265685900_bib43","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1182\/blood-2012-05-431452","article-title":"Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor","volume":"121","author":"Reinart","year":"2013","journal-title":"Blood"},{"issue":"3","key":"2022120116265685900_bib44","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/leu.2015.305","article-title":"Depletion of CLL-associated patrolling monocytes and macrophages controls disease development and repairs immune dysfunction in\u00a0vivo","volume":"30","author":"Hanna","year":"2016","journal-title":"Leukemia"},{"issue":"7","key":"2022120116265685900_bib45","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.1016\/j.celrep.2016.01.042","article-title":"Targeting macrophages sensitizes chronic lymphocytic leukemia to apoptosis and inhibits disease progression","volume":"14","author":"Galletti","year":"2016","journal-title":"Cell Rep"},{"issue":"4","key":"2022120116265685900_bib46","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.ccell.2016.09.007","article-title":"LYN kinase in the tumor microenvironment is essential for the progression of chronic lymphocytic leukemia","volume":"30","author":"Nguyen","year":"2016","journal-title":"Cancer Cell"},{"issue":"7718","key":"2022120116265685900_bib47","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41586-018-0290-0","article-title":"A\u00a0multiprotein supercomplex controlling oncogenic signalling in lymphoma","volume":"560","author":"Phelan","year":"2018","journal-title":"Nature"},{"issue":"12","key":"2022120116265685900_bib48","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.3324\/haematol.2016.157206","article-title":"CD40 signaling instructs chronic lymphocytic leukemia cells to attract monocytes via the CCR2 axis","volume":"102","author":"van Attekum","year":"2017","journal-title":"Haematologica"},{"issue":"11","key":"2022120116265685900_bib49","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1182\/blood-2013-10-529610","article-title":"Extracellular HMGB1 promotes differentiation of nurse-like cells in chronic lymphocytic leukemia","volume":"123","author":"Jia","year":"2014","journal-title":"Blood"},{"issue":"1","key":"2022120116265685900_bib50","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1182\/blood-2014-07-589069","article-title":"Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia","volume":"125","author":"Audrito","year":"2015","journal-title":"Blood"},{"issue":"1","key":"2022120116265685900_bib51","doi-asserted-by":"crossref","first-page":"4116","DOI":"10.1038\/s41467-019-12055-2","article-title":"Extracellular nicotinate phosphoribosyltransferase binds Toll like receptor 4 and mediates inflammation","volume":"10","author":"Manag\u00f2","year":"2019","journal-title":"Nat Commun"},{"issue":"24","key":"2022120116265685900_bib52","doi-asserted-by":"crossref","first-page":"6118","DOI":"10.1158\/1078-0432.CCR-15-3099","article-title":"Colony-stimulating factor-1 receptor is required for nurse-like cell survival in chronic lymphocytic leukemia","volume":"22","author":"Polk","year":"2016","journal-title":"Clin Cancer Res"},{"issue":"37","key":"2022120116265685900_bib53","doi-asserted-by":"crossref","first-page":"24576","DOI":"10.18632\/oncotarget.25191","article-title":"Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples","volume":"9","author":"Edwards","year":"2018","journal-title":"Oncotarget"},{"issue":"8","key":"2022120116265685900_bib54","doi-asserted-by":"crossref","first-page":"2655","DOI":"10.1182\/blood.V96.8.2655","article-title":"Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1","volume":"96","author":"Burger","year":"2000","journal-title":"Blood"},{"issue":"3","key":"2022120116265685900_bib55","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1182\/blood-2004-03-0889","article-title":"Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha","volume":"106","author":"Nishio","year":"2005","journal-title":"Blood"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/22\/2335\/2019254\/blood_bld-2022-016272-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/140\/22\/2335\/2019254\/blood_bld-2022-016272-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T19:01:14Z","timestamp":1669921274000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/140\/22\/2335\/486564\/Macrophage-and-BCR-derived-but-not-TLR-derived"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,1]]},"references-count":55,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2022,12,1]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2022016272","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,1]]}}}