Antileukemic activity of YPN-005, a CDK7 inhibitor, inducing apoptosis through c-MYC and FLT3 suppression in acute myeloid leukemia. Issue 10 (October 2022)

• Record Type: Journal Article
• Authors: Koo, Bon-Kwan; Choi, Eun-Ji; Hur, Eun-Hye; Moon, Ju Hyun; Kim, Ji Yun; Park, Han-Seung; Choi, Yunsuk; Lee, Jung-Hee; Lee, Kyoo-Hyung; Choi, Eun Kyung; Kim, Jinhwan; Lee, Je-Hwan
• Is Part Of: Heliyon. Volume 8:Issue 10(2022)
• Publication Date: 2022-10
• Subjects: Acute myeloid leukemia (AML) -- Cyclin dependent kinase 7 (CDK7) inhibitor -- c-MYC -- MCL1 -- FLT3; Research -- Periodicals; Medical sciences -- Periodicals; Natural history -- Periodicals; Social sciences -- Periodicals; Earth sciences -- Periodicals; Physical sciences -- Periodicals; 507.2
• DOI: 10.1016/j.heliyon.2022.e11004
• Languages: English
• ISSNs: 2405-8440

Abstract

Abstract: Acute myeloid leukemia (AML) is an aggressive blood cancer with a high rate of relapse associated with adverse survival outcomes, especially in elderly patients. An aberrant expression of cyclin dependent kinase 7 (CDK7) is associated with poor outcomes and CDK7 inhibition has showed antitumor activities in various cancers. We investigated the efficacy of YPN-005, a CDK7 inhibitor in AML cell lines, xenograft mouse model, and primary AML cells. YPN-005 effectively inhibited the proliferation of AML cells by inducing apoptosis and reducing phosphorylation of RNA polymerase II. The c-MYC expression decreased with treatment of YPN-005, and the effect of YPN-005 was negatively correlated with c-MYC expression. YPN-005 also showed antileukemic activities in primary AML cells, especially those harboring FMS-like tyrosine kinase 3–internal tandem duplication ( FLT3 -ITD) mutation and in in vivo mouse model. Phosphorylated FLT3/Signal transducer and activator of transcription 5 (STAT5) was decreased and FLT3 / STAT5 was downregulated with YPN-005 treatment. Our data suggest that YPN-005 has a role in treating AML by suppressing c-MYC and FLT3. Abstract : Acute myeloid leukemia (AML); Cyclin dependent kinase 7 (CDK7) inhibitor; c-MYC; MCL1, FLT3.