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.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis in patients with resistant or relapsed disease. Although NOTCH is a known driver in T-ALL, its clinical inhibition has significant limitations. Our previous studies suggested that NRARP, a negative regulator of Notch signaling, could have a suppressive role in T-ALL. Here, we report that NRARP levels are significantly increased in primary T-ALL cells suggesting that NRARP is not sufficient to block NOTCH oncogenic signals. Interestingly, although NRARP overexpression blocks NOTCH1 signaling and delays the proliferation of T-ALL cells that display high levels of Notch1 signaling, it promotes the expansion of T-ALL cells with lower levels of Notch1 activity. We found that NRARP interacts with lymphoid enhancer-binding factor 1 (LEF1) and potentiates Wnt signaling in T-ALL cells with low levels of Notch. Together these results indicate that NRARP plays a dual role in T-ALL pathogenesis, regulating both Notch and Wnt pathways, with opposite functional effects depending on Notch activity. Consistent with this hypothesis, mice transplanted with T-cells co-expressing NOTCH1 and NRARP develop leukemia later than mice transplanted with T-NOTCH1 cells. Importantly, mice transplanted with T-cells overexpressing NRARP alone developed leukemia with similar kinetics to those transplanted with T-NOTCH1 cells. Our findings uncover a role for NRARP in T-ALL pathogenesis and indicate that Notch inhibition may be detrimental for patients with low levels of Notch signaling, which would likely benefit from the use of Wnt signaling inhibitors. Importantly, our findings may extend to other cancers where Notch and Wnt play a role.
Signaling downstream of the IL7 receptor plays important physiological and pathological roles, including differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain of function mutations in the IL7Rα chain, the specific component of the receptor for IL7, result in constitutive, IL7-independent signaling and trigger acute lymphoblastic leukemia. Here, we show that loss of the phosphoinositide 5-phosphatase INPP5K is associated with increased levels of the INPP5K substrate PtdIns(4,5)P2 and causes altered dynamic structure of the IL7 receptor. We discovered that the IL7Rα chain contains a very conserved positively-charged polybasic amino acid sequence in its cytoplasmic juxtamembrane region; this region establishes stronger ionic interactions with negatively-charged PtdIns(4,5)P2 in the absence of INPP5K, freezing IL7Rα chain structure. This dynamic structural alteration causes defects in IL7 receptor signaling, culminating in decreased expression of EBF1 and PAX5 transcription factor, in microdomain formation, cytoskeletal reorganization and bone marrow B cell differentiation. Similar alterations following reduced INPP5K expression also impacted mutated, constitutively activated IL7Rα chains that trigger leukemia development, leading to reduced cell proliferation. Altogether, our results indicate that the lipid 5-phosphatase INPP5K hydrolyses plasma membrane PtdIns(4,5)P2, allowing the requisite conformational changes of the IL7Rα chain for optimal signaling.
Background:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Although outcome has improved throughout the years, the aggressive chemotherapeutic regimens required for treatment efficacy often lead to toxicities. Moreover, a significant fraction of T-ALL patients relapse and have extremely poor prognosis. MicroRNAs (miRs) are small non-coding RNAs (~22 nucleotides) that regulate gene expression. Importantly, specific miR expression profiles have been shown to distinguish between tumor and normal cells and tumors from different developmental origins and stages of differentiation.
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