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.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
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.
UR - http://www.scopus.com/inward/record.url?scp=85121306348&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27197-5
DO - 10.1038/s41467-021-27197-5
M3 - Article
C2 - 34907175
AN - SCOPUS:85121306348
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 7268
ER -
