Journal
LEUKEMIA
Volume 36, Issue 6, Pages 1533-1540Publisher
SPRINGERNATURE
DOI: 10.1038/s41375-022-01590-5
Keywords
-
Categories
Funding
- NIH [R01CA211734]
- MGH Research Scholar Award
- European Research Council, under the European Union [CoG-648455, PoC-862545]
- FCT [FAPESP/20015/2014, PTDC/MEC-HEM/31588/2017, PTDC/MEC-ONC/4606/2021]
- Fundação para a Ciência e a Tecnologia [FAPESP/20015/2014, PTDC/MEC-HEM/31588/2017, PTDC/MEC-ONC/4606/2021] Funding Source: FCT
Ask authors/readers for more resources
This study demonstrates the collaboration between mutant IL7R and Myc in inducing T-ALL and shows that mutant IL7R enriches for leukemia propagating potential.
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 alpha chain (IL-7R alpha, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available