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.
Highlights
Interleukin-7 receptor α is essential for lymphoid development
Using a FLEx switch strategy, we generated conditional mutant IL7R knock-in mice (Supplementary Fig. 2) that we crossed with CD2-Cre animals (Fig. 1a) to produce progeny in which recombination occurs at the common lymphoid progenitor (CLP) stage[24], allowing for physiological regulation of mutant IL7R expression in developing lymphoid cells
In our model, mutant IL7R expression is kept under physiological regulation—similar to what happens in human acute lymphoblastic leukemia (ALL), where no mutations in promoter, enhancer, or super-enhancer regions directly regulating IL7R have been reported
Summary
Interleukin-7 receptor α (encoded by IL7R) is essential for lymphoid development. We demonstrate that lymphoid-restricted mutant IL7R, expressed at physiological levels in conditional knock-in mice, establishes a preleukemic stage in which B-cell precursors display self-renewal ability, initiating leukemia resembling PAX5 P80R or Ph-like human B-ALL. 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. During B cell development, IL-7Rα signaling is tightly regulated and, together with the pre-BCR, sequentially coordinates proliferation and Ig gene rearrangements, in cross-talk with critical transcription factors such as PAX5, EBF1 or IKAROS8,9. 11) involves an IL-7 hypersensitive pre-leukemic stage, and IL-7Rα is required for B-ALL developing in mice from the combination of Stat[5] activation and Pax[5] haploinsufficiency[12] B-ALL arising in Pax5-deficient mice exposed to infection[10] or in mice with combined loss of Sh2b3 and Trp[53] (ref. 11) involves an IL-7 hypersensitive pre-leukemic stage, and IL-7Rα is required for B-ALL developing in mice from the combination of Stat[5] activation and Pax[5] haploinsufficiency[12]
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