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

doi:10.1016/j.isci.2021.102748

Reduced eIF4E function impairs B-cell leukemia without altering normal B-lymphocyte function

iScience. 2021 Jun 17;24(7):102748. doi: 10.1016/j.isci.2021.102748. eCollection 2021 Jul 23.

Authors

Honyin Chiu¹, Roberta Buono¹, Leandra V Jackson¹, Lee-Or Herzog¹, Sharmila Mallya¹, Crystal S Conn^{2

3}, Davide Ruggero^{2

3

4}, David A Fruman¹

Affiliations

¹ Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
³ School of Medicine and Department of Urology, University of California, San Francisco, CA 94143, USA.
⁴ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.

Abstract

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.

Keywords: cancer; cell biology; molecular biology.