Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia.
Animals
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cell Survival
/ genetics
Gain of Function Mutation
Heterozygote
Homozygote
Humans
Interleukin-7 Receptor alpha Subunit
/ genetics
Mice
Penetrance
Precancerous Conditions
/ genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
Precursor Cells, B-Lymphoid
/ pathology
Proto-Oncogene Proteins p21(ras)
/ genetics
Signal Transduction
/ drug effects
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 12 2021
14 12 2021
Historique:
received:
22
04
2020
accepted:
03
11
2021
entrez:
15
12
2021
pubmed:
16
12
2021
medline:
11
1
2022
Statut:
epublish
Résumé
Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. Whether acute lymphoblastic leukemia (ALL)-related IL7R gain-of-function mutations can trigger leukemogenesis remains unclear. Here, we demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a pre-leukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. Full transformation associates with transcriptional upregulation of oncogenes such as Myc or Bcl2, downregulation of tumor suppressors such as Ikzf1 or Arid2, and major IL-7R signaling upregulation (involving JAK/STAT5 and PI3K/mTOR), required for leukemia cell viability. Accordingly, maximal signaling drives full penetrance and early leukemia onset in homozygous IL7R mutant animals. Notably, we identify 2 transcriptional subgroups in mouse and human Ph-like ALL, and show that dactolisib and sphingosine-kinase inhibitors are potential treatment avenues for IL-7R-related cases. Our model, a resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.
Identifiants
pubmed: 34907175
doi: 10.1038/s41467-021-27197-5
pii: 10.1038/s41467-021-27197-5
pmc: PMC8671594
doi:
Substances chimiques
Antineoplastic Agents
0
Interleukin-7 Receptor alpha Subunit
0
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7268Subventions
Organisme : NCI NIH HHS
ID : R35 CA197695
Pays : United States
Informations de copyright
© 2021. The Author(s).
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