Stage-specific Arf tumor suppression in Notch1-induced T-cell acute lymphoblastic leukemia.
Frequent hallmarks of T-cell acute lymphoblastic leukemia (T-ALL) include aberrant NOTCH signaling and deletion of the CDKN2A locus, which contains 2 closely linked tumor suppressor genes (INK4A and ARF). When bone marrow cells or thymocytes transduced with a vector encoding the constitutively activated intracellular domain of Notch1 (ICN1) are expanded ex vivo under conditions that support T-cell development, cultured progenitors rapidly induce CD4+/CD8+ T-ALLs after infusion into healthy syngeneic mice. Under these conditions, enforced ICN1 expression also drives formation of T-ALLs in unconditioned CD-1 nude mice, bypassing any requirements for thymic maturation. Retention of Arf had relatively modest activity in suppressing the formation of T-ALLs arising from bone marrow-derived ICN1+ progenitors in which the locus is epigenetically silenced, and all resulting Arf (+/+) tumors failed to express the p19(Arf) protein. In striking contrast, retention of Arf in thymocyte-derived ICN1+ donor cells significantly delayed disease onset and suppressed the penetrance of T-ALL. Use of cultured thymocyte-derived donor cells expressing a functionally null Arf-GFP knock-in allele confirmed that ICN1 signaling can induce Arf expression in vivo. Arf activation by ICN1 in T cells thereby provides stage-specific tumor suppression but also a strong selective pressure for deletion of the locus in T-ALL.
Volanakis
Emmanuel J
EJ
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Williams
Richard T
RT
Sherr
Charles J
CJ
D019264:Adoptive Transfer; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014161:Transduction, Genetic; D014162:Transfection
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1