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bioRxiv · 10.1101/2025.02.10.637540

Posttranscriptional activity of the eukaryotic translation initiation factoreIF4E contributes to HoxA9-driven leukemogenesis

Zhou, F.·Kraljacic, B. C.·Bach, C.·Feng, L.·Mishima, Y.·Borden, K. L. B.·Tenen, D. G.
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Abstract

HoxA9, a homeodomain-containing transcription factor, is mis-expressed in over half of acute myeloid leukemia (AML) cases, and is associated with poor prognosis. Previous studies indicated that HoxA9 binds to the eukaryotic translation initiation factor eIF4E in primary specimens and that HoxA9 stimulated the RNA export and translation efficiency of selected RNAs via eIF4E. However, the relevance of this to its leukemogenic transformation capacity was unknown. Here, we used a double point mutation (HoxA9AA) to disrupt the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature. Surprisingly, the mutation dramatically increased AML latency from a median of 90 to 280 days and resulted in incomplete penetrance. Re-transplantation of bone marrow cells from leukemic animals demonstrated even more pronounced differences in disease kinetics and penetrance with all animals succumbing to disease by day 60 in the wildtype group, while some HoxA9AA mice never developed leukemia. Collectively, these findings uncover a novel, transcription-independent mechanism of HoxA9-driven leukemogenesis through eIF4E and positions eIF4E as a potential therapeutic target AML patients expressing high levels of HoxA9. Key PointsO_LIA double point mutation in HoxA9 disrupted the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature. C_LIO_LIEukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis and is important for the maintenance of acute myeloid leukemia. C_LI

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Zhou, F., Kraljacic, B. C., Bach, C., Feng, L., Mishima, Y., Borden, K. L. B., Tenen, D. G.. 2025-02-12. Posttranscriptional activity of the eukaryotic translation initiation factoreIF4E contributes to HoxA9-driven leukemogenesis. https://doi.org/10.1101/2025.02.10.637540

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