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Growth inhibition and suppression of the mTOR and Wnt/β‐catenin pathways in T‐acute lymphoblastic leukemia by rapamycin and MYCN depletion
Author(s) -
Kong Desheng,
Fan Shengjin,
Sun Lili,
Chen Xi,
Zhao Yanqiu,
Zhao Linlin,
Guo Zhibo,
Li Yinghua
Publication year - 2021
Publication title -
hematological oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 44
eISSN - 1099-1069
pISSN - 0278-0232
DOI - 10.1002/hon.2831
Subject(s) - pi3k/akt/mtor pathway , wnt signaling pathway , cancer research , downregulation and upregulation , small interfering rna , gene knockdown , sirolimus , rptor , apoptosis , biology , cell cycle , mechanistic target of rapamycin , cell growth , cell cycle checkpoint , signal transduction , microbiology and biotechnology , cell culture , transfection , gene , biochemistry , genetics
T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive malignancy. Understanding of the molecular pathogenesis may lead to novel therapeutic targets. Rapamycin, the mammalian target of rapamycin (mTOR) inhibitor, showed inhibitory effects on T‐ALL cells. In this study, we showed that rapamycin significantly reduced MYCN mRNA and protein in a concentration‐dependent manner in T‐ALL cells. Selective knockdown of MYCN by small interfering RNA had similar effects to rapamycin to inhibit T‐ALL proliferation and colony formation and to induce G1‐phase cell‐cycle arrest and apoptosis. The inhibitory effects of rapamycin and MYCN depletion were also found in a Molt‐4 xenograft model. Rapamycin and MYCN inhibition suppressed both Wnt/β‐catenin and mTOR signaling pathways. The results suggest the effects of rapamycin on adult T‐ALL is likely mediated by downregulation of MYCN . The findings suggest MYCN a potential target for the treatment of adult T‐ALL. Additionally, dual targeting of mTOR and Wnt/β‐catenin pathways may represent a novel strategy in the treatment of adult T‐ALL.