Translation Initiation Represents an Acute Myeloid Leukemia Cell Vulnerability That Can Be Co-Targeted With BCL-2 Inhibition
Lee, Y. S.; Good, J. D.; Awais, N.; Eschle, B. K.; Lineberry, M. S.; Teo, J. L.; Bibeau, S.; Wollman, M.; Karadimov, G.; Sariipek, N.; Acosta, J.; Noel, J.; Cucchi, D.; DePasquale, E. A. K.; Gokhale, P. C.; Najm, F. J.; Stone, R. M.; Garcia, J. S.; Lane, A. A.; van Galen, P.
Show abstract
Targeted therapies like Venetoclax have increased the options available to acute myeloid leukemia (AML) patients, but survival remains poor due to drug resistance and disease relapse. We found that the translation initiation factor EIF4A1, which unwinds complex mRNA structures in the 5 UTR of oncogenic transcripts, is highly expressed in AML stem- and progenitor-like cells. Inhibiting eIF4A with the small molecule Zotatifin reduces translation of transcripts related to the cell cycle and survival. This results in downregulation of AKT, STAT-5, and MCL-1 and underlies synergy of Zotatifin with Venetoclax. The drug combination promotes apoptosis across AML genotypes, while the effect on healthy blood cells is limited. Using in vivo relapsed and refractory AML patient-derived xenograft models, the combination significantly suppressed tumor burden and prolonged survival of xenografted mice. These results support eIF4A-mediated protein translation as a therapeutic target in AML. SIGNIFICANCEDespite advances in targeted therapies, the 5-year survival rate for acute myeloid leukemia remains around 32%. The efficacy of existing treatments may be improved with the addition of Zotatifin, an inhibitor targeting the translation initiation factor eIF4A.
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