An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells

Hayatigolkhatmi, K., Padroni, G., Su, W., Fang, L., Gómez-Castañeda, E., Hsieh, Y.C., Jackson, L., Pellicano, F., Burley, G.A. and Jørgensen, H.G. (2019) An investigation of targeted inhibition of transcription factor activity with pyrrole imidazole polyamide (PA) in chronic myeloid leukemia (CML) blast crisis cells. Bioorganic and Medicinal Chemistry Letters, 29(18), pp. 2622-2625. (doi: 10.1016/j.bmcl.2019.07.049) (PMID:31378570)

Abstract

Tyrosine kinase inhibitor (TKI) therapy is the standard treatment for chronic phase (CP)-chronic myeloid leukemia (CML), yet patients in blast crisis (BC) phase of CML are unlikely to respond to TKI therapy. The transcription factor E2F1 is a down-stream target of the tyrosine kinase BCR-ABL1 and is up-regulated in TKI-resistant leukemia stem cells (LSC). Pyrrole imidazole polyamides (PA) are minor groove binders which can be programmed to target DNA sequences in a gene-selective manner. This manuscript describes such an approach with a PA designed to down-regulate E2F1 controlled gene expression by targeting a DNA sequence within 100 base pairs (bp) upstream of the E2F1 consensus sequence. Human BC-CML KCL22 cells were assessed after treatment with PA, TKI or their combination. Our PA inhibited BC-CML cell expansion based on cell density analysis compared to an untreated control after a 48-hour time-course of PA treatment. However, no evidence of cell cycle arrest was observed among BC-CML cells treated with PA, with respect to their no drug control counterparts. Thus, this work demonstrates that PAs are effective in inhibiting E2F1 TF activity which results in a temporal reduction in BC-CML cell number. We envisage that PAs could be used in the future to map genes under E2F1 control in CML LSCs.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jorgensen, Dr Heather and Gómez Castañeda, Eduardo and Pellicano, Dr Francesca and Hsieh, Dr Ya-Ching
• Authors: Hayatigolkhatmi, K., Padroni, G., Su, W., Fang, L., Gómez-Castañeda, E., Hsieh, Y.C., Jackson, L., Pellicano, F., Burley, G.A., and Jørgensen, H.G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Bioorganic and Medicinal Chemistry Letters
• Publisher: Elsevier
• ISSN: 0960-894X
• ISSN (Online): 1464-3405
• Published Online: 27 July 2019
• Copyright Holders: Copyright © 2019 Elsevier Ltd.
• First Published: First published in Bioorganic and Medicinal Chemistry Letters 29(18):2622-2625
• Publisher Policy: Reproduced in accordance with the publisher copyright policy