Tungsten Blocks Murine B Lymphocyte Differentiation and Proliferation Through Downregulation of IL-7 Receptor/Pax5 Signaling

Toxicol Sci. 2019 Jul 1;170(1):45-56. doi: 10.1093/toxsci/kfz080.


Tungsten is an emerging environmental toxicant associated with several pediatric leukemia clusters, although a causal association has not been established. Our previous work demonstrated that tungsten exposure resulted in an accumulation of pre-B cells in the bone marrow, the same cell type that accumulates in pediatric acute lymphoblastic leukemia (ALL). To better understand the relevant molecular mechanisms, we performed RNA-sequencing on flow sorted pre-B cells from control and tungsten-exposed mice. Tungsten decreased the expression of multiple genes critical for B cell development, including members of the interleukin-7 receptor (IL-7R) and pre-B cell receptor signaling pathways, such as Jak1, Stat5a, Pax5, Syk, and Ikzf3. These results were confirmed in an in vitro model of B cell differentiation, where tungsten arrested differentiation at the pro-B cell stage and inhibited proliferation. These changes were associated with decreased expression of multiple genes in the IL-7R signaling pathway and decreased percentage of IL-7R, phosphorylated STAT5 double-positive cells. Supplementation with IL-7 or overexpression of Pax5, the transcription factor downstream of IL-7R, rescued the tungsten-induced differentiation block. Together, these data support the hypothesis that IL-7R/Pax5 signaling axis is critical to tungsten-mediated effects on pre-B cell development. Importantly, many of these molecules are modulated in ALL.

Keywords: B lymphocyte; Differentiation; IL-7R; Pax5; Tungsten.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Differentiation / drug effects*
  • Cell Proliferation / drug effects*
  • Down-Regulation
  • Gene Expression / drug effects
  • Male
  • Mice, Inbred C57BL
  • PAX5 Transcription Factor / genetics
  • PAX5 Transcription Factor / metabolism*
  • Receptors, Interleukin-7 / genetics
  • Receptors, Interleukin-7 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Tungsten Compounds / toxicity*


  • PAX5 Transcription Factor
  • Pax5 protein, mouse
  • Receptors, Interleukin-7
  • Tungsten Compounds
  • sodium tungstate(VI)