Flavopiridol induces BCL-2 expression and represses oncogenic transcription factors in leukemic blasts from adults with refractory acute myeloid leukemia

Abstract

Flavopiridol is a cyclin-dependent kinase inhibitor that induces cell cycle arrest, apoptosis, and clinical responses in selected patients with acute myeloid leukemia (AML). A better understanding of the molecular pathways targeted by flavopiridol is needed to design optimal combinatorial therapy. Here, we report that in vivo administration of flavopiridol induced expression of the BCL-2 anti-apoptotic gene in leukemic blasts from adult patients with refractory AML. Moreover, flavopiridol repressed the expression of genes encoding oncogenic transcription factors (HMGA1, STAT3, E2F1) and the major subunit of RNA Polymerase II. Our results provide mechanistic insight into the cellular pathways targeted by flavopiridol. Although further studies are needed, our findings also suggest that blocking anti-apoptotic pathways could enhance cytotoxicity with flavopiridol.

Keywords:

• Flavopiridol
• acute myeloid leukemia
• BCL-2
• HMGA1
• STAT3
• E2F1

Acknowledgements

The authors wish to thank the Sidney Kimmel Cancer Center specimen accession core staff for collecting and banking the samples used in our study. We also thank the following funding agencies: NIH RO1 CA092339; The Leukemia & Lymphoma Scholar Award 1694-06 (L. M. S. Resar); Alex’s Lemonade Stand Foundation Award (L. M. S. Resar and J. Hillion); The Maryland Stem Cell Research Fund (L. M. S. Resar, J. Hillion, and B. Joseph); J. P. McCarthy Foundation (L. M. S. Resar and J. E. Karp); NCI Co-operative Agreement U01 CA70095 (J. E. Karp); NCI Cancer Center Support Grant P30 069773-45 (J. E. Karp); philanthropic funds from Dr. Robert E. Fischell (in memory of his wife, Mariam) (J. E. Karp); and the Prevent Cancer Foundation (J. Hillion).

Potential conflict of interest:

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