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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., Competing Interests: Research funding to S.A.P. has been provided from 10.13039/100014491Pharmacyclics, 10.13039/501100013650MorphoSys, Janssen, 10.13039/100004325AstraZeneca, 10.13039/100013252TG Therapeutics, 10.13039/100006436Celgene, 10.13039/100006483AbbVie, 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, 10.13039/100006436Celgene, 10.13039/100004328Genentech, 10.13039/100014491Pharmacyclics, 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., (© 2020 The Author(s).)