Chronic Lymphocytic Leukemia B-cell-derived TNFα Impairs Bone Marrow Myelopoiesis

Overview

Journal iScience

Publisher Cell Press

Date 2021 Jan 18

PMID 33458625

Citations 5

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

Affiliations

Soon will be listed here.

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 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.

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