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

• DOI: 10.1016/j.isci.2021.102748
• Publication Date: 2021-06-17T10:04:34Z
• Authors: Honyin Chiu; Roberta Buono; Leandra V. Jackson; Lee-or Herzog; Sharmila Mallya; Crystal S. Conn; Davide Ruggero; David A. Fruman
• Keywords: Pediatric; 0301 basic medicine; Biomedical and Clinical Sciences; Childhood Leukemia; Pediatric Cancer; Science; Oncology and Carcinogenesis; Q; 610; Hematology; Biological Sciences; Article; 3. Good health; 03 medical and health sciences; Rare Diseases; cell biology; Genetics; 2.1 Biological and endogenous factors; molecular biology; cancer; Biochemistry and Cell Biology; Cancer

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.