PUBLICATION
Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia
- Authors
- Oliveira, M.L., Veloso, A., Garcia, E.G., Iyer, S., Pereira, C., Barreto, V.M., Langenau, D.M., Barata, J.T.
- ID
- ZDB-PUB-220519-3
- Date
- 2022
- Source
- Leukemia 36(6): 1533-1540 (Journal)
- Registered Authors
- Langenau, David
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Carcinogenesis/metabolism
- Child
- Humans
- Interleukin-7 Receptor alpha Subunit/metabolism
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/pathology
- Receptors, Interleukin-7/genetics
- Receptors, Interleukin-7/metabolism
- Signal Transduction/genetics
- T-Lymphocytes/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 35581375 Full text @ Leukemia
Citation
Oliveira, M.L., Veloso, A., Garcia, E.G., Iyer, S., Pereira, C., Barreto, V.M., Langenau, D.M., Barata, J.T. (2022) Mutant IL7R collaborates with MYC to induce T-cell acute lymphoblastic leukemia. Leukemia. 36(6):1533-1540.
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive pediatric cancer. Amongst the wide array of driver mutations, 10% of T-ALL patients display gain-of-function mutations in the IL-7 receptor α chain (IL-7Rα, encoded by IL7R), which occur in different molecular subtypes of this disease. However, it is still unclear whether IL-7R mutational activation is sufficient to transform T-cell precursors. Also, which genes cooperate with IL7R to drive leukemogenesis remain poorly defined. Here, we demonstrate that mutant IL7R alone is capable of inducing T-ALL with long-latency in stable transgenic zebrafish and transformation is associated with MYC transcriptional activation. Additionally, we find that mutant IL7R collaborates with Myc to induce early onset T-ALL in transgenic zebrafish, supporting a model where these pathways collaborate to drive leukemogenesis. T-ALLs co-expressing mutant IL7R and Myc activate STAT5 and AKT pathways, harbor reduced numbers of apoptotic cells and remake tumors in transplanted zebrafish faster than T-ALLs expressing Myc alone. Moreover, limiting-dilution cell transplantation experiments reveal that activated IL-7R signaling increases the overall frequency of leukemia propagating cells. Our work highlights a synergy between mutant IL7R and Myc in inducing T-ALL and demonstrates that mutant IL7R enriches for leukemia propagating potential.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping