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IL7R mutational activation can initiate Ph-like and PAX5 P80R 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-leukemia stage in which B-cell precursors display self-renewal ability, initiating precursor B-ALL that resembles PAX5 P80R or Ph-like human leukemia. 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 both 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 novel treatment avenues for IL-7R-related cases. Our model, a unique resource to explore the pathophysiology and therapeutic vulnerabilities of B-ALL, demonstrates that IL7R can initiate this malignancy.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): B Cell, Bone Marrow

DISEASE(S): Acute Leukemia

SUBMITTER: Andrew Howden

LAB HEAD: Professor João T. Barata

PROVIDER: PXD017147 | Pride | 2021-11-02

REPOSITORIES: Pride

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Publications

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

Almeida Afonso R M ARM Neto João L JL Cachucho Ana A Euzébio Mayara M Meng Xiangyu X Kim Rathana R Fernandes Marta B MB Raposo Beatriz B Oliveira Mariana L ML Ribeiro Daniel D Fragoso Rita R Zenatti Priscila P PP Soares Tiago T de Matos Mafalda R MR Corrêa Juliana Ronchi JR Duque Mafalda M Roberts Kathryn G KG Gu Zhaohui Z Qu Chunxu C Pereira Clara C Pyne Susan S Pyne Nigel J NJ Barreto Vasco M VM Bernard-Pierrot Isabelle I Clappier Emannuelle E Mullighan Charles G CG Grosso Ana R AR Yunes J Andrés JA Barata João T JT

Nature communications 20211214 1

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 transfor ...[more]

PMID: 34907175

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Project description:The Rosa-rtTAnls/tetO-HoxA10 mouse model is a Tetracycline-On (tetO) system in which the expression level of HoxA10 can be tightly regulated and overexpressed under administration of the Doxycycline (Doxy) in the drinking bottle of mice or fed with Ciproxine (Cipro) as a negative control of HoxA10 expression. In this experiment, we analyzed molecular karyotype derived from CGH arrays analysis of HoxA10 Acute Myeloid Leukemia (AML) cells induced in primary recipient mice (1ary) and in secondary recipient mice, with HoxA10 overexpression (DOXY) or after turning off the HoxA10 overexpression (CIPRO). Concerning the biological design, we compared leukemia induced in primary recipient mice (1ary) to normal bone marrow (normal control). We compared also primary leukemia (1ary) to leukemia induced in secondary recipient mice induce by continuous expression of HoxA10 (Doxy). Finally we compared leukemia induced in secondary recipient mice induce by continuous expression of HoxA10 (Doxy) to leukemia induced in secondary recipient mice after turning off expression of HoxA10 (Cipro) to analyse relapse growth of leukemic cells after turning off HoxA10. Concerning the protocol, the leukemic cells originated from two independent primary AML donor mice (cl1 and cl2) are injected in secondary recipient mice, which are monitored for reoccurrence of leukemia. AML are induced by Doxycycline (Doxy) or Ciproxine as negative control (Cipro), by administration of 0.2g/mL continuously in the drinking bottle until development of AML. In sick mice, femurs and tibias were removed and cleaned of soft tissue, bones were crushed, and the cell suspension was filtered over a 100-m pore size cell strainer filter (Falcon; Becton Dickinson). Total DNA from BM cells of Cipro and Doxy receiving recipient mice suffering from leukemia was extracted from bone marrow cells (Qiagen). DNA concentration and integrity were respectively determined by NanoDrop spectrophotometry (NanoDrop technologies) and a Bioanalyser (Agilent technology). Hybridization to Mouse CGH microarray 244A (Agilent) were performed by the Atlas Biolabs (Germany).

Dataset Information

IL7R mutational activation can initiate Ph-like and PAX5 P80R precursor B-cell acute lymphoblastic leukemia

Publications

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

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