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

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.

Targeting STAT3 and STAT5 in Cancer

“…Additionally, STAT3 (and not STAT5B) mutations were identified in multiple peripheral T-cell lymphomas (PTCL), as well as high pY-STAT3 expression, particularly in angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) patient samples, two different PTCL cancer types [26]. From an inhibition perspective, a derivatized indole was shown to be effective in both chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), as well as aggressive STAT5-N642H tumors [27]. Collectively, these studies shed light on the importance of STAT3/5 in several hematopoietic cancers, potentially offering disease biomarkers and hallmarks across several different indications.…”

Inhibitors Targeting STAT5 Signaling in Myeloid Leukemias: New Tetrahydroquinoline Derivatives with Improved Antileukemic Potential

“…We showed that 17 f suppressed P−Y‐STAT5 and growth of CML and AML cells [41] . We also demonstrated that 17 f sensitizes leukemic cells that acquired resistance to IM or Ara‐C [42] …”

“…We previously showed that 17 f overcomes the resistance of CML and AML cells to IM and Ara‐C [42] . We then ask whether 7 a and 7 a’ had a greater impact than 17 f to overcome the resistance of CML cells to IM.…”

“…Results showed that 7 a and 7 a’ had no effect on STAT5A and STAT5B mRNA levels in leukemic cells treated for 15 h with these compounds (Figure 3A). We then analyzed the phosphorylation and expression of STAT5 in KU812 and MV4‐11 cells exposed to 7 a and 7 a’ (3 μM) for 24 and 48 h. Results showed that both compounds inhibited the phosphorylation of STAT5 and reduced STAT5 protein expression at 48 h post‐treatment suggesting that 7 a and 7 a’ as 17 f might indirectly interfere with the stability/degradation of the proteins (Figure 3B) [42] . Further investigations are then required to determine impact of these molecules on the ubiquitin/proteasome system.…”

Acriflavine targets oncogenic STAT5 signaling in myeloid leukemia cells

“…inhibitor associated with IM suppresses the growth of IM-resistant CML cells by blocking STAT5B protein expression. 41 Importantly, we showed that ACF-mediated effects on STAT3/ STAT5 occur via a BCR-ABL-independent mechanism. We found that ACF alone neither affects the phosphorylation nor the expression of this TKO in IM-sensitive cells, even though minor, but cell death but also cellular senescence.…”