The purpose of this study was to investigate the effect of specific Mcl-1 small interference RNA (siRNA) on the proliferation and chemosensitivity of U-937 AML cell to etoposide.
Using dynamic BH3 profiling, we show that the agent TG02, which downregulates MCL-1, sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide in acute myeloid leukaemia (AML) cells.
Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.
Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia.
Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML.<b>Conclusions:</b> The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML.<i></i>.
Venetoclax/GDC-0980 coadministration induced rapid and pronounced BAX mitochondrial translocation, cytochrome c release, and apoptosis in various AML cell lines in association with AKT/mTOR inactivation and MCL-1 downregulation; ectopic expression of MCL-1 significantly protected cells from this regimen.
Cyclin-dependent kinase 9 (CDK9), a transcriptional activator necessary for the expression of MCL-1, represents a promising target for future AML therapies.
Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML.<i>See related commentary by Leber et al., p. 1511</i>.<i>This article is highlighted in the In This Issue feature, p. 1494</i>.
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.
These results indicate that Bcl-2/Bcl-X<sub>L</sub> and Mcl-1 act in a redundant fashion as effectors of BMM-mediated AML drug resistance and highlight the potential of Mcl-1-repression to revert BMM-mediated drug resistance in the leukemic stem cell population, thus, prevent disease relapse and ultimately improve patient survival.
We have recently revealed that FLT3-ITD confers resistance to the PI3K/AKT pathway inhibitors by protecting the mTORC1/4EBP1/Mcl-1 pathway through Pim kinases induced by STAT5 activation in AML.
Here, we review the role of MCL-1 in AML and the mechanisms by which the potent cyclin-dependent kinase 9 inhibitor alvocidib, through regulation of MCL-1, may serve as a rational therapeutic approach against the disease.
Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML.
No statistically significant differences were found between the studied genes and prognosis stratifications, but Bcl-xl, Bak, cIAP1, and Mcl-1, LC3 were expressed at lower levels in the unfavorable AML group compared to the controls.
By comparing the expression levels of one probe with known sequences from each of the three genes, we identified several key genes, induced myeloid leukemia cell differentiation protein (Mcl1), far upstream element-binding protein 1 (Fubp1), and tumor protein D52-like 2 (Tpd52l2), which play important roles in acute lymphocytic leukemia and acute myelocytic leukemia.