Although in vitro resistance of leukemia cell lines correlated with expression of the prosurvival protein Mcl-1, there was no relationship between Mcl-1 expression and in vivo xenograft response to ABT-737.
Overexpression of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic protein, is associated with tumor progression and drug resistance in leukemia and several cancers.
We determined the level of 8-OHdG formation by HPLC-ECD, and the expression of iNOS and mechanism of cell death signaling (including nuclear factor-kappaB(NFkappaB), MEKK-1, Caspase 3, B Cell lymphomal leukemia-2 (Bcl-2), inhibitor of apoptosis protein (IAP) and myeloid cell leukemia-1 (Mcl-1)) by Western-blot assay.
Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines.
Amplification and overexpression of the myeloid cell leukemia differentiation protein MCL1 and the murine double minute protein MDM2 have been reported in various human tumors as well as hematological malignancies including acute myeloid leukemia (AML).
Overexpression of myeloid cell leukaemia-1 (Mcl-1) and Survivin is associated with drug resistance, tumour progression and inhibition of apoptotic mechanisms in leukaemia and several cancers.
Since EAT/mcl1 is mapped to 1q21 near the breakpoint in the JTs, high level expression of EAT/mcl1 may be associated with the poor prognosis of leukemia with JTs.
The anti-apoptotic factors Mcl-1, Bcl-2, and Bcl-xL were also found to be over-expressed in acute myeloid leukemia (AML) (Kaufmann et al., 2016) and acute lymphocytic leukemia (ALL) (Findley, Gu, Yeager, & Zhou, 1997), suggesting that dis-regulated apoptotic processes could be a factor in the instigation of leukemia and/or its relapse.
In other MM and leukemia cell lines, COLO677, OPM2, and U937, the ribosomal genes were less prone to epigenetic heterogeneity as compared to the c-myc and Mcl-1 proto-oncogenes.
We further demonstrate that strategies to inhibit MCL-1 expression potentiate the proapoptotic action of BCL-2 inhibitors in both mouse and human BCR-ABL(+) leukemia cell lines.
The protein expression levels of B‑cell lymphoma 2 (BCL2) and myeloid cell leukemia sequence 1 (MCL1) were also compared between transfected and wild‑type HLE‑B3 cells by western blot analysis.
A common insertional polymorphism in promoter of MCL1, a member of BCL2 family gene with the dual regulatory functions, has been shown to be functional in leukemia, but its association with cancer predisposition and prognosis has not been well established.
Together, these findings demonstrate that BAY 43-9006 mediates cell death in human leukemia cells, at least in part, through down-regulation of Mcl-1 via inhibition of translation.