| First Author | Zhang Y | Year | 2020 |
| Journal | Biochem Biophys Res Commun | Volume | 524 |
| Issue | 4 | Pages | 1018-1024 |
| PubMed ID | 32063363 | Mgi Jnum | J:306302 |
| Mgi Id | MGI:6712398 | Doi | 10.1016/j.bbrc.2020.02.021 |
| Citation | Zhang Y, et al. (2020) Miltefosine suppression of Pten null T-ALL leukemia via beta-catenin degradation through inhibition of pT308-Akt and TGFbeta1/Smad3. Biochem Biophys Res Commun 524(4):1018-1024 |
| abstractText | Pten deletion in the hematopoietic stem cells (HSC) causes a myeloproliferative disorder, which may subsequently develop into a T-cell acute lymphoblastic leukemia (T-ALL). beta-catenin expression was dramatically increased in the c-Kit(mid)CD3(+)Lin(-) leukemia stem cells (LSC) and was critical for T-ALL development. Therefore, the inactivation of beta-catenin in LSC may have a potential to eliminate the LSC. In this study, we investigated the mechanism of enhancement of the beta-catenin expression and subsequently used a drug to inactivate beta-catenin expression in T-ALL. Western blot (WB) analysis revealed an increased level of beta-catenin in the leukemic cells, but not in the pre-leukemic cells. Furthermore, the WB analysis of the thymic cells from different stages of leukemia development showed that increased expression of beta-catenin was not via the pS9-GSK3beta signaling, but was dependent on the pT308-Akt activation. Miltefosine (Hexadecylphosphocholine) is the first oral anti-Leishmania drug, which is a phospholipid agent and has been shown to inhibit the PI3K/Akt activity. Treatment of the Pten(Delta/Delta) leukemic mice with Miltefosine for different durations demonstrated that the pT308-Akt and the beta-catenin expressions were inhibited in the leukemia blast cells. Miltefosine treatment also suppressed the TGFbeta1/Smad3 signaling pathway. Analysis of TGFbeta1 in the sorted subpopulations of the blast cells showed that TGFbeta1 was secreted by the CD3(+)CD4(-) subpopulation and may exert effects on the subpopulations of both CD3(+)CD4(+) and CD3(+)CD4(-) leukemia blast cells. When a TGFbetaR1 inhibitor, SB431542 was injected into the Pten(Delta/Delta) leukemic mice, the Smad3 and beta-catenin expressions were down-regulated. On the basis of the results, we conclude that Miltefosine can suppress leukemia by degrading beta-catenin through repression of the pT308-Akt and TGFbeta1/Smad3 signaling pathways. This study demonstrates a possibility to inhibit Pten loss-associated leukemia genesis via targeting Akt and Smad3. |
