FOXM1 in Cancer: Interactions and Vulnerabilities.
- Andrei L Gartel
- Cancer research
CnB1fl/Δ or CnB1Δ/Δ leukemic cells (Figure 2c, d0). Dasatinib (10 mg/kg/day) was administered to the remaining recipients and three mice per group were killed 1, 2 or 6 days after the start of treatment to monitor tumor load. After 1 day of treatment, no significant decrease in tumor load was observed. In contrast, at day 2, no GFP+ leukemic cells were detected in the spleen and liver, while tumor load in BM was decreased with, however, no significant difference between mice injected with CnB1fl/Δ or CnB1Δ/Δ leukemic cells (Figure 2c, d2). After 6 days of treatment, leukemic cells were absent from the BM, spleen and liver of all recipients (Figure 2c, d6). Thus, in this in vivo setting, Cn-deficient cells did not show increased sensitivity to dasatinib treatment as compared to their Cn-proficient counterparts. In T-ALL, Cn impinges upon leukemic cell survival, proliferation and migration, and is critical to leukemia-propagating activity in mice. In contrast, Cn is dispensable for BCR-ABLinduced B-ALL maintenance and propagation as none of these traits are affected by genetic ablation of Cn function in distinct mouse models. Yet, the survival, proliferation and migratory activity of Cn-deficient B-ALL remain inhibited by CsA, and CsA still sensitized these cells to TKI cytotoxic effects. Cn is thus not the critical target of CsA cooperation with TKI. CsA activity relies upon its binding to at least six members of the cyclophilin family of peptidyl-prolyl isomerases (PPIases) and inhibits their prolyl cis/trans isomerization activity. Recent evidence shows that cis/trans isomerization of a number of proteins, including growth factor receptors, adaptors and transcription factors, functions as a molecular switch to regulate their activity. Deregulation of these pathways is likely instrumental in the emerging role of cyclophilins in cancer development and resistance to treatment. Identification of CsA-sensitive cyclophilin substrates or, possibly, recently described direct CsA protein targets involved in leukemic cell survival and proliferation, and relevant to sensitization to TKI responses, will provide new therapeutic options in Ph+ B-ALL treatment.