PMID- 30912803
OWN - NLM
STAT- MEDLINE
DCOM- 20200724
LR  - 20200724
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 170
IP  - 1
DP  - 2019 Jul 1
TI  - Tungsten Blocks Murine B Lymphocyte Differentiation and Proliferation Through 
      Downregulation of IL-7 Receptor/Pax5 Signaling.
PG  - 45-56
LID - 10.1093/toxsci/kfz080 [doi]
AB  - 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.
CI  - (c) The Author(s) 2019. Published by Oxford University Press on behalf of the 
      Society of Toxicology. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Wu, Ting Hua
AU  - Wu TH
AD  - Lady Davis Institute for Medical Research.
AD  - Department of Experimental Medicine.
FAU - Bolt, Alicia M
AU  - Bolt AM
AD  - Lady Davis Institute for Medical Research.
AD  - Department of Oncology.
FAU - Chou, Hsiang
AU  - Chou H
AD  - Lady Davis Institute for Medical Research.
AD  - Department of Experimental Medicine.
FAU - Plourde, Dany
AU  - Plourde D
AD  - Lady Davis Institute for Medical Research.
FAU - De Jay, Nicolas
AU  - De Jay N
AD  - Lady Davis Institute for Medical Research.
AD  - Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
FAU - Guilbert, Cynthia
AU  - Guilbert C
AD  - Lady Davis Institute for Medical Research.
FAU - Young, Yoon Kow
AU  - Young YK
AD  - Lady Davis Institute for Medical Research.
FAU - Kleinman, Claudia L
AU  - Kleinman CL
AD  - Lady Davis Institute for Medical Research.
AD  - Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
FAU - Mann, Koren K
AU  - Mann KK
AD  - Lady Davis Institute for Medical Research.
AD  - Department of Experimental Medicine.
AD  - Department of Oncology.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (PAX5 Transcription Factor)
RN  - 0 (Pax5 protein, mouse)
RN  - 0 (Receptors, Interleukin-7)
RN  - 0 (Tungsten Compounds)
RN  - 64LRH4405G (sodium tungstate(VI))
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/*drug effects/metabolism/pathology
MH  - Cell Differentiation/*drug effects
MH  - Cell Proliferation/*drug effects
MH  - Down-Regulation
MH  - Gene Expression/drug effects
MH  - Male
MH  - Mice, Inbred C57BL
MH  - PAX5 Transcription Factor/genetics/*metabolism
MH  - Receptors, Interleukin-7/genetics/*metabolism
MH  - Signal Transduction/drug effects/genetics
MH  - Tungsten Compounds/*toxicity
OTO - NOTNLM
OT  - B lymphocyte
OT  - Differentiation
OT  - IL-7R
OT  - Pax5
OT  - Tungsten
EDAT- 2019/03/27 06:00
MHDA- 2020/07/25 06:00
CRDT- 2019/03/27 06:00
PHST- 2019/03/27 06:00 [pubmed]
PHST- 2020/07/25 06:00 [medline]
PHST- 2019/03/27 06:00 [entrez]
AID - 5420169 [pii]
AID - 10.1093/toxsci/kfz080 [doi]
PST - ppublish
SO  - Toxicol Sci. 2019 Jul 1;170(1):45-56. doi: 10.1093/toxsci/kfz080.