PUBLICATION
In vivo impact of JAK3 A573V mutation revealed using zebrafish
- Authors
- Basheer, F., Bulleeraz, V., Ngo, V.Q.T., Liongue, C., Ward, A.C.
- ID
- ZDB-PUB-220528-6
- Date
- 2022
- Source
- Cellular and molecular life sciences : CMLS 79: 322 (Journal)
- Registered Authors
- Liongue, Clifford, Ward, Alister C.
- Keywords
- Cytokine receptor signaling, JAK3, Leukemia, Lymphocytes, Zebrafish
- MeSH Terms
-
- Animals
- Janus Kinase 3*/genetics
- Janus Kinase 3*/metabolism
- Mutation/genetics
- STAT5 Transcription Factor*/genetics
- STAT5 Transcription Factor*/metabolism
- Signal Transduction/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 35622134 Full text @ Cell. Mol. Life Sci.
Citation
Basheer, F., Bulleeraz, V., Ngo, V.Q.T., Liongue, C., Ward, A.C. (2022) In vivo impact of JAK3 A573V mutation revealed using zebrafish. Cellular and molecular life sciences : CMLS. 79:322.
Abstract
Background Janus kinase 3 (JAK3) acts downstream of the interleukin-2 (IL-2) receptor family to play a pivotal role in the regulation of lymphoid cell development. Activating JAK3 mutations are associated with a number of lymphoid and other malignancies, with mutations within the regulatory pseudokinase domain common.
Methods The pseudokinase domain mutations A572V and A573V were separately introduced into the highly conserved zebrafish Jak3 and transiently expressed in cell lines and zebrafish embryos to examine their activity and impact on early T cells. Genome editing was subsequently used to introduce the A573V mutation into the zebrafish genome to study the effects of JAK3 activation on lymphoid cells in a physiologically relevant context throughout the life-course.
Results Zebrafish Jak3 A573V produced the strongest activation of downstream STAT5 in vitro and elicited a significant increase in T cells in zebrafish embryos. Zebrafish carrying just a single copy of the Jak3 A573V allele displayed elevated embryonic T cells, which continued into adulthood. Hematopoietic precursors and NK cells were also increased, but not B cells. The lymphoproliferative effects of Jak3 A573V in embryos was shown to be dependent on zebrafish IL-2Rγc, JAK1 and STAT5B equivalents, and could be suppressed with the JAK3 inhibitor Tofacitinib.
Conclusions This study demonstrates that a single JAK3 A573V allele expressed from the endogenous locus was able to enhance lymphopoiesis throughout the life-course, which was mediated via an IL-2Rγc/JAK1/JAK3/STAT5 signaling pathway and was sensitive to Tofacitinib. This extends our understanding of oncogenic JAK3 mutations and creates a novel model to underpin further translational investigations.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping