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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number101994
JournaliScience
Volume24
Issue number1
DOIs
StatePublished - Jan 22 2021

Keywords

  • Immunology
  • Molecular Biology
  • Stem Cells Research

ASJC Scopus subject areas

  • General

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