Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia

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 lev...

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Published in:Nature communications Vol. 12; no. 1; pp. 7268 - 16
Main Authors: Almeida, Afonso R. M., Neto, João L., Cachucho, Ana, Euzébio, Mayara, Meng, Xiangyu, Kim, Rathana, Fernandes, Marta B., Raposo, Beatriz, Oliveira, Mariana L., Ribeiro, Daniel, Fragoso, Rita, Zenatti, Priscila P., Soares, Tiago, de Matos, Mafalda R., Corrêa, Juliana Ronchi, Duque, Mafalda, Roberts, Kathryn G., Gu, Zhaohui, Qu, Chunxu, Pereira, Clara, Pyne, Susan, Pyne, Nigel J., Barreto, Vasco M., Bernard-Pierrot, Isabelle, Clappier, Emannuelle, Mullighan, Charles G., Grosso, Ana R., Yunes, J. Andrés, Barata, João T.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 14.12.2021
Nature Publishing Group
Nature Portfolio
Subjects:
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Acute lymphoblastic leukemia
Animal models
Animals
Antineoplastic Agents - pharmacology
Cell Line, Tumor
Cell Survival - genetics
Cell viability
Cytokines
Gain of Function Mutation
Heterozygote
Homozygote
Humanities and Social Sciences
Humans
Interleukin 7
Interleukin 7 receptors
Interleukin-7 Receptor alpha Subunit - genetics
Interleukin-7 Receptor alpha Subunit - metabolism
Kinases
Leukemia
Leukemogenesis
Life Sciences
Lymphatic leukemia
Lymphocytes B
Malignancy
Mice
multidisciplinary
Mutants
Mutation
Myc protein
Pax5 protein
Penetrance
Precancerous Conditions - genetics
Precancerous Conditions - pathology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology
Precursor Cells, B-Lymphoid - pathology
Precursors
Proto-Oncogene Proteins p21(ras) - genetics
Receptors
Science
Science (multidisciplinary)
Signal Transduction - drug effects
Signaling
Stat5 protein
Subgroups
Suppressors
TOR protein
Transcription
Tumors
ISSN:2041-1723, 2041-1723
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Summary: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. Interleukin-7 receptor alpha (IL7Ra) is important for lymphoid cell development but its role in leukaemogenesis is not clear. Here, the authors generate a knock-in murine model to show that activating mutations in IL7Ra can initiate precursor B-cell acute lymphoblastic leukaemia.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-021-27197-5