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
Affiliations
Bryce A. Manso
Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
Jordan E. Krull
Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
Kimberly A. Gwin
Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
Petra K. Lothert
Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA
Baustin M. Welch
Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905, USA
Anne J. Novak
Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
Sameer A. Parikh
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
Neil E. Kay
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA
Kay L. Medina
Department of Immunology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905, USA; Corresponding author
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.
