A Novel Inhibitor of STAT5 Signaling Overcomes Chemotherapy Resistance in Myeloid Leukemia Cells.

Marie Brachet-Botineau,Frédéric Mazurier,Marie-Claude Viaud-Massuard,Marion Polomski,Olivier Hérault,Nicolas Vallet,Gildas Prié,Fabrice Gouilleux,Ludovic Juen,Margaux Deynoux

doi:10.3390/cancers11122043

Abstract

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote the resistance of CML cells to tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM). We recently synthesized and discovered a new inhibitor (17f) with promising antileukemic activity. 17f selectively inhibits STAT5 signaling in CML and AML cells by interfering with the phosphorylation and transcriptional activity of these proteins. In this study, the effects of 17f were evaluated on CML and AML cell lines that respectively acquired resistance to IM and cytarabine (Ara-C), a conventional therapeutic agent used in AML treatment. We showed that 17f strongly inhibits the growth and survival of resistant CML and AML cells when associated with IM or Ara-C. We also obtained evidence that 17f inhibits STAT5B but not STAT5A protein expression in resistant CML and AML cells. Furthermore, we demonstrated that 17f also targets oncogenic STAT5B N642H mutant in transformed hematopoietic cells.

Highlights

STAT5A and STAT5B are two closely related signal transducers and activators of transcription family members
We demonstrated that 17f treatment reduces STAT5B protein levels in resistant chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cells, suggesting that 17f overcomes chemotherapy resistance though the downregulation of this protein
Western blot analysis clearly evidenced that STAT5B protein expression was decreased after combination treatments suggesting that 17f sensitizes K562R cells to imatinib mesylate (IM) treatment by targeting STAT5B protein (Figure 4C)

Summary

Introduction

STAT5A and STAT5B are two closely related signal transducers and activators of transcription family members. Both proteins are crucial downstream effectors of tyrosine kinase oncogenes (TKO). Such as Fms-like receptor tyrosine kinase 3 with internal tandem duplications (Flt3-ITD), BCR-ABL and JAK2V617F which cause AML, CML and other myeloproliferative diseases (MPD), respectively [1]. The development of tyrosine kinase inhibitors (TKI) targeting BCR-ABL such as imatinib mesylate (IM) has revolutionized the treatment of CML. Despite this success story, IM is not totally curative and approximately 50% of patients remain therapy-free after IM discontinuation. The occurrence of BCR-ABL mutations in progressive or relapsed disease promotes IM resistance of CML cells [6]

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Conclusion