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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.

Recent evidence suggests that neural stem cell (NSC) fate is highly dependent on mitochondrial bioenergetics. Tauroursodeoxycholic acid (TUDCA), an endogenous neuroprotective bile acid and a metabolic regulator, stimulates NSC proliferation and enhances adult NSC pool in vitro and in vivo. In this study, we dissected the mechanism triggered by this proliferation-inducing molecule, namely in mediating metabolic reprogramming. Liquid chromatography coupled with mass spectrometry (LC-MS) based detection of differential proteomics revealed that TUDCA reduces the mitochondrial levels of the long-chain acyl-CoA dehydrogenase (LCAD), an enzyme crucial for β-oxidation of long-chain fatty acids (FA). TUDCA impact on NSC mitochondrial proteome was further confirmed, including in neurogenic regions of adult rats. We show that LCAD raises throughout NSC differentiation, while its silencing promotes NSC proliferation. In contrast, nuclear levels of sterol regulatory element-binding protein (SREBP-1), a major transcription factor of lipid biosynthesis, changes in the opposite manner of LCAD, being upregulated by TUDCA. In addition, alterations in some metabolic intermediates, such as palmitic acid, also supported the TUDCA-induced de novo lipogenesis. More interestingly, a metabolic shift from FA to glucose catabolism appears to occur in TUDCA-treated NSCs, since mitochondrial levels of pyruvate dehydrogenase E1-α (PDHE1-α) were significant enhanced by TUDCA. At last, the mitochondria-nucleus translocation of PDHE1-α was potentiated by TUDCA, associated with an increase of H3-histones and acetylated forms. In conclusion, TUDCA-induced proliferation of NSCs involves metabolic plasticity and mitochondria-nucleus crosstalk, in which nuclear PDHE1-α might be required to assure pyruvate-derived acetyl-CoA for histone acetylation and NSC cycle progression.

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