FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphocytic leukemia (J Clin Invest, 2007, doi:10.1172/JCI31095)

報告日期: 2007/10/05
報告時間: 17:10/18:00
報告學生: 吳正偉
講評老師: 沈孟儒
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FTY720, a new alternative for treating blast crisis chronic myelogenous leukemia and Philadelphia chromosome–positive acute lymphocytic leukemia

 

J Clin Invest. 2007, 117(9): 2408–2421.

 

Student: 吳正偉                                

Time: 1710-1800, 10/05/07                        

Commentator: 沈孟儒 教授

Place: ROOM 602

 

Abstract:

BCR-ABL is a chimeric oncoprotein that exhibits deregulated tyrosine kinase activity of ABL and is implicated in the pathogenesis of Philadelphia chromosome-positive human leukemias such as blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome–positive acute lymphocytic leukemia (Ph1 ALL). Furthermore, the activity of protein phosphatase 2A (PP2A) in these leukemia cell lines is much lower than its parental cells. FTY 720, an analogue of sphingosine, is not only an immunomodulator which has been applied to prolong allograft survival but also playing as a PP2A activator and as an anticancer agent which has been proposed for treating many solid tumors. In addition, FTY 720 has been shown to induce apoptosis in lymphocytes and some leukemia cell lines. Here, the authors demonstrate that FTY720 induces apoptosis and impairs clonogenicity of p210/p190BCR/ABL myeloid and lymphoid cell lines and CML-BCCD34+ and Ph1 ALLCD34+/CD19+ progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190BCR/ABL-driven leukemogenesis without exerting adverse effects. These observations are caused by re-activating the PP2A activity instead of sphingosine signaling pathway. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.

 

 

Reference:

1.          Matsuoka, Y., et al., A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells. Br J Pharmacol, 2003. 138(7): p. 1303-12.

2.          Smith, D.L., J. Burthem, and A.D. Whetton, Molecular pathogenesis of chronic myeloid leukaemia. Expert Rev Mol Med, 2003. 5(27): p. 1-27.