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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Vydané v:	Nature communications Ročník 12; číslo 1; s. 7268 - 16
Hlavní autori:	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.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	London Nature Publishing Group UK 14.12.2021 Nature Publishing Group Nature Portfolio
Predmet:	1-Phosphatidylinositol 3-kinase 13/31 13/95 38 38/77 38/91 42/44 45 631/67/1990/283/2125 631/67/395 631/67/70 64/110 692/4017 692/4028/67/1990/283/2125 82/58 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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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-27197-5