Evidence for activated Lck protein tyrosine kinase as the driver of proliferation in acute myeloid leukemia cell, CTV-1. (March 2019)

• Record Type: Journal Article
• Authors: Li, Li; Cui, Yixin; Shen, Jinyan; Dobson, Hannah; Sun, Gongqin
• Is Part Of: Leukemia research. Volume 78(2019)
• Page Start: 12
• Page End: 20
• Publication Date: 2019-03
• Subjects: Acute myeloid leukemia -- Lck protein tyrosine kinase -- Driver mutations -- Driver of proliferation -- CTV-1; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2019.01.006
• Languages: English
• ISSNs: 0145-2126

Abstract

Highlights: The proliferation of CTV-1 AML cells are potently inhibited by Lck kinase inhibitors. CTV-1 lysate contains Lck kinase activity. Lck gene in CTV-1 is over-expressed, and contains four mutations. Two of the mutations disrupt negative regulation to activate Lck. The first natural cell line driven by a constitutively activated Src family kinase. Abstract: Acute myeloid leukemia (AML) is a heterogeneous group of fast growing cancers of myeloid progenitor cells, for which effective treatments are still lacking. Identification of signaling inhibitors that block their proliferation could reveal the proliferative mechanism of a given leukemia cell, and provide small molecule drugs for targeted therapy for AML. In this study, kinase inhibitors that block the majority of cancer signaling pathways are evaluated for their inhibition of two AML cell lines of the M5 subtypes, CTV-1 and THP-1. While THP-1 cells do not respond to any of these inhibitors, CTV-1 cells are potently inhibited by dasatinib, bosutinib, crizotinib, A-770041, and WH-4-23, all potent inhibitors for Lck, a Src family kinase. CTV-1 cells contain a kinase activity that phosphorylates an Lck-specific peptide substrate in an Lck inhibitor-sensitive manner. Furthermore, the Lck gene is over-expressed in CTV-1, and it contains four mutations, two of which are located in regions critical for Lck negative regulation, and are confirmed to activate Lck. Collectively, these results provide strong evidence that mutated and overexpressed Lck is driving CTV-1 proliferation. While Lck activation and overexpression is rare in AML, this study provides a potential therapeutic strategy for treating patients with a similar oncogenic mechanism.