Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling.
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.
Brown
Valerie I
VI
Division of Oncology, Children's Hospital of Philadelphia, and University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Fang
Junjie
J
Alcorn
Keith
K
Barr
Rosalind
R
Kim
Jenny M
JM
Wasserman
Robert
R
Grupp
Stephan A
SA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D015851:Interleukin-7 / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D015851:Interleukin-7; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus