Chiu Honyin, Buono Roberta, Jackson Leandra V, Herzog Lee-Or, Mallya Sharmila, Conn Crystal S, Ruggero Davide, Fruman David A
Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
iScience. 2021 Jun 17;24(7):102748. doi: 10.1016/j.isci.2021.102748. eCollection 2021 Jul 23.
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 germline and conditional knockout models to assess the impact of reduced 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 impairs transformation and reduces fitness in competition assays and . In contrast, reduced 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.
帽结合蛋白真核生物起始因子4E（eIF4E）促进与增殖和存活相关的mRNA的翻译，是癌症治疗的一个有吸引力的靶点。在这里，我们使用种系和条件性敲除模型来评估基因剂量降低对B细胞白血病发生的影响，并与对正常前B细胞和成熟B细胞功能的影响进行比较。使用BCR-ABL驱动的前B细胞白血病模型，我们发现在竞争试验中，一个等位基因的缺失会损害转化并降低适应性。相比之下，基因剂量的降低对前B细胞和成熟B细胞的发育或对未转化的B谱系细胞的存活或增殖没有显著影响。这些结果表明，抑制eIF4E可能是前B细胞白血病的一种新的治疗工具，同时保留正常B细胞的发育和功能。
