Chronic lymphocytic leukemia B-cell-derived TNFα impairs bone marrow myelopoiesis

• Main Authors: Bryce A. Manso, Jordan E. Krull, Kimberly A. Gwin, Petra K. Lothert, Baustin M. Welch, Anne J. Novak, Sameer A. Parikh, Neil E. Kay, Kay L. Medina
• Format: Article
• Language: English
• Published: Elsevier 2021-01-01
• Series: iScience
• Subjects: Molecular Biology; Immunology; Stem Cells Research
• Online Access: http://www.sciencedirect.com/science/article/pii/S2589004220311913

Summary: 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.