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

Afonso R M Almeida; João L Neto; Ana Cachucho; Mayara Euzébio; Xiangyu Meng; Rathana Kim; Marta B Fernandes; Beatriz Raposo; Mariana L Oliveira; Daniel Ribeiro; Rita Fragoso; Priscila P Zenatti; Tiago Soares; Mafalda R de Matos; Juliana Ronchi Corrêa; Mafalda Duque; Kathryn G Roberts; Zhaohui Gu; Chunxu Qu; Clara Pereira; Susan Pyne; Nigel J Pyne; Vasco M Barreto; Isabelle Bernard-Pierrot; Emannuelle Clappier; Charles G Mullighan; Ana R Grosso; J Andrés Yunes; João T Barata

doi:10.1038/s41467-021-27197-5

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

Afonso R M Almeida, João L Neto, Ana Cachucho, Mayara Euzébio, Xiangyu Meng, Rathana Kim, Marta B Fernandes, Beatriz Raposo, Mariana L Oliveira, Daniel Ribeiro, Rita Fragoso, Priscila P Zenatti, Tiago Soares, Mafalda R de Matos, Juliana Ronchi Corrêa, Mafalda Duque, Kathryn G Roberts, Zhaohui Gu, Chunxu Qu, Clara PereiraSusan Pyne, Nigel J Pyne, Vasco M Barreto, Isabelle Bernard-Pierrot, Emannuelle Clappier, Charles G Mullighan, Ana R Grosso, J Andrés Yunes, João T Barata

Strathclyde Institute Of Pharmacy And Biomedical Sciences

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Abstract

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.

Original language	English
Article number	7268
Number of pages	16
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27197-5
Publication status	Published - 14 Dec 2021

Keywords

Cell Line, Tumor
Animals
Humans
Mice
Precancerous Conditions
Antineoplastic Agents
Signal Transduction
Cell Survival
Heterozygote
Homozygote
Penetrance
Proto-Oncogene Proteins p21(ras)
Interleukin-7 Receptor alpha Subunit
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
Precursor Cells, B-Lymphoid
Gain of Function Mutation

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Almeida-etal-NC-2021-mutational-activation-can-initiate-precursor-B-cell-acute-lymphoblastic-leukemiaFinal published version, 5 MBLicence: CC BY 4.0

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Almeida, A. R. M., Neto, J. L., Cachucho, A., Euzébio, M., Meng, X., Kim, R., Fernandes, M. B., Raposo, B., Oliveira, M. L., Ribeiro, D., Fragoso, R., Zenatti, P. P., Soares, T., de Matos, M. R., Corrêa, J. R., Duque, M., Roberts, K. G., Gu, Z., Qu, C., ... Barata, J. T. (2021). Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia. Nature Communications, 12(1), Article 7268 . https://doi.org/10.1038/s41467-021-27197-5

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title = "Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia",

abstract = "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.",

keywords = "Cell Line, Tumor, Animals, Humans, Mice, Precancerous Conditions, Antineoplastic Agents, Signal Transduction, Cell Survival, Heterozygote, Homozygote, Penetrance, Proto-Oncogene Proteins p21(ras), Interleukin-7 Receptor alpha Subunit, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Gain of Function Mutation",

author = "Almeida, {Afonso R M} and Neto, {Jo{\~a}o L} and Ana Cachucho and Mayara Euz{\'e}bio and Xiangyu Meng and Rathana Kim and Fernandes, {Marta B} and Beatriz Raposo and Oliveira, {Mariana L} and Daniel Ribeiro and Rita Fragoso and Zenatti, {Priscila P} and Tiago Soares and {de Matos}, {Mafalda R} and Corr{\^e}a, {Juliana Ronchi} and Mafalda Duque and Roberts, {Kathryn G} and Zhaohui Gu and Chunxu Qu and Clara Pereira and Susan Pyne and Pyne, {Nigel J} and Barreto, {Vasco M} and Isabelle Bernard-Pierrot and Emannuelle Clappier and Mullighan, {Charles G} and Grosso, {Ana R} and Yunes, {J Andr{\'e}s} and Barata, {Jo{\~a}o T}",

year = "2021",

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day = "14",

doi = "10.1038/s41467-021-27197-5",

language = "English",

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journal = "Nature Communications",

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Almeida, ARM, Neto, JL, Cachucho, A, Euzébio, M, Meng, X, Kim, R, Fernandes, MB, Raposo, B, Oliveira, ML, Ribeiro, D, Fragoso, R, Zenatti, PP, Soares, T, de Matos, MR, Corrêa, JR, Duque, M, Roberts, KG, Gu, Z, Qu, C, Pereira, C, Pyne, S, Pyne, NJ, Barreto, VM, Bernard-Pierrot, I, Clappier, E, Mullighan, CG, Grosso, AR, Yunes, JA & Barata, JT 2021, 'Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia', Nature Communications, vol. 12, no. 1, 7268 . https://doi.org/10.1038/s41467-021-27197-5

TY - JOUR

T1 - Interleukin-7 receptor α mutational activation can initiate precursor B-cell acute lymphoblastic leukemia

AU - Almeida, Afonso R M

AU - Neto, João L

AU - Cachucho, Ana

AU - Euzébio, Mayara

AU - Meng, Xiangyu

AU - Kim, Rathana

AU - Fernandes, Marta B

AU - Raposo, Beatriz

AU - Oliveira, Mariana L

AU - Ribeiro, Daniel

AU - Fragoso, Rita

AU - Zenatti, Priscila P

AU - Soares, Tiago

AU - de Matos, Mafalda R

AU - Corrêa, Juliana Ronchi

AU - Duque, Mafalda

AU - Roberts, Kathryn G

AU - Gu, Zhaohui

AU - Qu, Chunxu

AU - Pereira, Clara

AU - Pyne, Susan

AU - Pyne, Nigel J

AU - Barreto, Vasco M

AU - Bernard-Pierrot, Isabelle

AU - Clappier, Emannuelle

AU - Mullighan, Charles G

AU - Grosso, Ana R

AU - Yunes, J Andrés

AU - Barata, João T

PY - 2021/12/14

Y1 - 2021/12/14

N2 - 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.

AB - 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.

KW - Cell Line, Tumor

KW - Animals

KW - Humans

KW - Mice

KW - Precancerous Conditions

KW - Antineoplastic Agents

KW - Signal Transduction

KW - Cell Survival

KW - Heterozygote

KW - Homozygote

KW - Penetrance

KW - Proto-Oncogene Proteins p21(ras)

KW - Interleukin-7 Receptor alpha Subunit

KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

KW - Precursor Cells, B-Lymphoid

KW - Gain of Function Mutation

U2 - 10.1038/s41467-021-27197-5

DO - 10.1038/s41467-021-27197-5

M3 - Article

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7268

ER -

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

Abstract

Keywords

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