Reduced eIF4E function impairs B-cell leukemia without altering normal B-lymphocyte function
Honyin Chiu,
Roberta Buono,
Leandra V. Jackson,
Lee-or Herzog,
Sharmila Mallya,
Crystal S. Conn,
Davide Ruggero,
David A. Fruman
Affiliations
Honyin Chiu
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA
Roberta Buono
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA
Leandra V. Jackson
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA
Lee-or Herzog
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA
Sharmila Mallya
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA
Crystal S. Conn
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA; School of Medicine and Department of Urology, University of California, San Francisco, CA 94143, USA
Davide Ruggero
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA; School of Medicine and Department of Urology, University of California, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA
David A. Fruman
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA; Corresponding author
Summary: The cap-binding protein eukaryotic initiation factor 4E (eIF4E) promotes translation of mRNAs associated with proliferation and survival and is an attractive target for cancer therapeutics. Here, we used Eif4e germline and conditional knockout models to assess the impact of reduced Eif4e gene dosage on B-cell leukemogenesis compared to effects on normal pre-B and mature B-cell function. Using a BCR-ABL-driven pre-B-cell leukemia model, we find that loss of one allele of Eif4e impairs transformation and reduces fitness in competition assays in vitro and in vivo. In contrast, reduced Eif4e gene dosage had no significant effect on development of pre-B and mature B cells or on survival or proliferation of non-transformed B lineage cells. These results demonstrate that inhibition of eIF4E could be a new therapeutic tool for pre-B-cell leukemia while preserving development and function of normal B cells.
