Chronic Lymphocytic Leukemia B-Cell-Derived Tnf Alpha Impairs Bone Marrow Myelopoiesis

TNF alpha is implicated in chronic lymphocytic leukemia (CLL) immunosuppression and disease progression. TNF alpha 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 TNF alpha abrogated upregulation of PU.1, yet restoration of GATA-2 required TNF alpha 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 TNF alpha. These findings implicate CLL B-cell-derived TNF alpha in impaired BM myelopoiesis.