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Updated: Aug 29, 2026
Development and Application of Rapamycin-regulated Tyrosine Phosphatases
Published on: September 6, 2024
Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated
Valerie I Brown1, Junjie Fang, Keith Alcorn
1Division of Oncology, Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Abstract:
A balance between survival and apoptotic signals regulates B cell development. These signals are tightly regulated by a host of molecules, including IL-7. Abnormal signaling events may lead to neoplastic transformation of progenitor B cells. Signal transduction inhibitors potentially may modulate these abnormal signals. Inhibitors of the mammalian target of rapamycin (mTOR) such as rapamycin have been used as immunosuppressive agents. We hypothesized that rapamycin might demonstrate activity against B-precursor acute lymphoblastic leukemia. We have found that rapamycin inhibited growth of B-precursor acute lymphoblastic leukemia lines in vitro, with evidence of apoptotic cell death. This growth inhibition was reversible by IL-7. One candidate as a signaling intermediate cross-regulated by rapamycin and IL-7 was p70 S6 kinase. Rapamycin also demonstrated in vivo activity in E mu-ret transgenic mice, which develop pre-B leukemia/lymphoma: E mu-ret transgenic mice with advanced disease treated daily with rapamycin as a single agent showed a >2-fold increase in length of survival as compared with symptomatic littermates who received vehicle alone. These results suggest that mammalian target of rapamycin inhibitors may be effective agents against leukemia and that one of the growth signals inhibited by this class of drugs in precursor B leukemic cells may be IL-7-mediated.
Insights
Rapamycin, an mTOR inhibitor, halts B-precursor acute lymphoblastic leukemia cell growth and induces apoptosis. This effect is reversible by IL-7, suggesting mTOR inhibitors as potential leukemia treatments.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- B cell development relies on a balance of survival and apoptotic signals, tightly regulated by molecules like IL-7.
- Aberrant signaling can lead to neoplastic transformation of progenitor B cells.
- Signal transduction inhibitors offer potential therapeutic avenues for modulating these abnormal signals.
Purpose of the Study:
- To investigate the efficacy of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, against B-precursor acute lymphoblastic leukemia (B-ALL).
- To explore the role of IL-7 in mediating resistance or sensitivity to mTOR inhibition in B-ALL.
- To assess the in vivo activity of rapamycin in a relevant preclinical model of B-ALL.
Main Methods:
- In vitro studies using B-ALL cell lines to assess rapamycin's effect on cell growth and apoptosis.
- Experiments to determine if IL-7 can reverse rapamycin-induced growth inhibition.
- In vivo studies in Eμ-ret transgenic mice, a model for pre-B leukemia/lymphoma, to evaluate rapamycin's impact on survival.
Main Results:
- Rapamycin significantly inhibited the growth of B-ALL cell lines in vitro, inducing apoptotic cell death.
- IL-7 was found to reverse the growth-inhibitory effects of rapamycin.
- Rapamycin treatment led to a greater than two-fold increase in survival in Eμ-ret transgenic mice with advanced disease.
Conclusions:
- mTOR inhibitors, such as rapamycin, show potential as effective therapeutic agents against B-ALL.
- IL-7-mediated signaling may represent a critical pathway targeted by mTOR inhibitors in precursor B leukemic cells.
- p70 S6 kinase is a potential signaling intermediate cross-regulated by rapamycin and IL-7.
