Leukemia, characterized by rearrangement of the mixed lineage leukemia (MLL) gene, is a highly aggressive cancer. And the infant leukemia is particularly common. However, the cure rate of infant leukemia has been stagnant in recent years. The occurrence of MLL gene rearrangement is a prognostic factor for high-risk diseases. MLL-r leukemia is characterized by a reciprocal translocation involving the MLL gene, which interferes with the normal function of the MLL1 protein. The dysregulated expression of HOXA9 and MEIS1 in hematopoietic progenitor cells can lead to leukemia. In fact, CMYC, BCL2 and NF-κB pathways also play a role in the survival of MLL-r leukemia cells. Obviously, there is an urgent need for more selective and targeted treatment of MLL-rearranged (MLL-r) leukemia to improve overall survival.
CCI-007 possesses anti-cancer activity against infant leukemia with MLL rearrangements. CCI-007 can selectively reduce the viability of a subset of MLL-r leukemia cells, as well as CALM-AF10 and SET-NUP214 leukemia cells. It does not affect normal cells, solid tumor lines and other MLL-wt leukemia cells. In addition, within 24 hours, CCI-007 induces a rapid caspase-dependent apoptosis through mitochondrial depolarization. Moreover, this compound also alters the characteristic MLL-r gene expression characteristics in sensitive cells, for example, the expression of HOXA9, MEIS1, CMYC and BCL2 is down-regulated. Compared with CCI-007 sensitive MLL-r leukemia cells, CCI-007 resistant MLL-r leukemia cells have significantly higher levels of MEIS1 and BCL2 gene expression. These findings provide an exciting provide an exciting new way for the treatment of these aggressive forms of leukemia.
To sum up, CCI-007 is an inhibitor that selectively targets a subset of MLL-r leukemia cell lines, and inhibits the viability of CALM-AF10 and SET-NUP214 leukemia.
References:
[1] Klaartje Somers, et al. Oncotarget. 2016 Jul 19;7(29):46067-46087.