@article{3a255261d0634391aed1cdfba36c3739,
title = "Chronic lymphocytic leukemia B-cell-derived TNFα impairs bone marrow myelopoiesis",
abstract = "TNFα is implicated in chronic lymphocytic leukemia (CLL) immunosuppression and disease progression. TNFα is constitutively produced by CLL B cells and is a negative regulator of bone marrow (BM) myelopoiesis. Here, we show that co-culture of CLL B cells with purified normal human hematopoietic stem and progenitor cells (HSPCs) directly altered protein levels of the myeloid and erythroid cell fate determinants PU.1 and GATA-2 at the single-cell level within transitional HSPC subsets, mimicking ex vivo expression patterns. Physical separation of CLL cells from control HSPCs or neutralizing TNFα abrogated upregulation of PU.1, yet restoration of GATA-2 required TNFα neutralization, suggesting both cell contact and soluble-factor-mediated regulation. We further show that CLL patient BM myeloid progenitors are diminished in frequency and function, an effect recapitulated by chronic exposure of control HSPCs to low-dose TNFα. These findings implicate CLL B-cell-derived TNFα in impaired BM myelopoiesis.",
keywords = "Immunology, Molecular Biology, Stem Cells Research",
author = "Manso, {Bryce A.} and Krull, {Jordan E.} and Gwin, {Kimberly A.} and Lothert, {Petra K.} and Welch, {Baustin M.} and Novak, {Anne J.} and Parikh, {Sameer A.} and Kay, {Neil E.} and Medina, {Kay L.}",
note = "Funding Information: We thank Dr. Susan Slager for statistical advice and Susan Schwager for providing CLL patient data. The Mayo Clinic Department of Hematology specimen processing and the Predolin biobanking team provided many of the samples utilized in this study. We also thank Matthew Holets and the Mayo Clinic Charlton Clinical Research and Trials Unit for assisting with donor recruitment and sample collection. This study was supported by Mayo Clinic NIH Grant Relief funding to K.L.M. and NIH T32 funding (NIH T32 AI07425-23) awarded to B.A.M. B.A.M. K.L.M. and N.E.K. wrote the manuscript. B.A.M. K.A.G. P.K.L. and B.M.W. performed and analyzed all experiments. J.E.K. provided expertise with the R program and assisted with UMAP generation. All authors reviewed and contributed to manuscript revisions. Research funding to S.A.P. has been provided from Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Celgene, AbbVie, and Ascentage Pharma for clinical studies in which S.A.P. is a principal investigator. S.A.P. also participated in Advisory Board meetings of Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie (he was not personally compensated for his participation). Research funding to N.E.K. has been provided from Acerta Pharma BV, Celgene, Genentech, Pharmacyclics, and Tolero Pharmaceutical. N.E.K. also participates in the data safety monitoring committees of Agios Pharm, Astra Zeneca, Celgene, Cytomx Therapeutics, Genentech, Infinity Pharm, Morpho-Sys, and Pharmacyclics (he was not personally compensated for his participation). All other authors declare no competing interests. Funding Information: We thank Dr. Susan Slager for statistical advice and Susan Schwager for providing CLL patient data. The Mayo Clinic Department of Hematology specimen processing and the Predolin biobanking team provided many of the samples utilized in this study. We also thank Matthew Holets and the Mayo Clinic Charlton Clinical Research and Trials Unit for assisting with donor recruitment and sample collection. This study was supported by Mayo Clinic NIH Grant Relief funding to K.L.M. and NIH T32 funding ( NIH T32 AI07425-23 ) awarded to B.A.M. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2021",
month = jan,
day = "22",
doi = "10.1016/j.isci.2020.101994",
language = "English (US)",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "1",
}