Turk J Hematol. 2025; 42(2): 82-91 | DOI: 10.4274/tjh.galenos.2024.2025.0292

The IRF2-INPP4B Pathway Aggravates Acute Myeloid Leukemia

Xiangqin Xing¹, Mei Zhang¹, Shengfen Tan¹, Junfeng Zhu², Jiajia Li², Pingping Zhang², Yuan Yuan², Meng Wang¹, Feng Zhang^1
1Bengbu Medical University, Department of Hematology, Bengbu, P.R. China
²The First Affiliated Hospital of Bengbu Medical University, Department of Hematology, Bengbu, P.R. China

Objective: Interferon-regulatory factor 2 (IRF2) and inositol polyphosphate 4-phosphatase B (INPP4B) are indispensable for differentiating immune T-cells, but the regulatory principle of the IRF2-INPP4B signaling channel in the apoptosis of acute myeloid leukemia (AML) cells remains unclear. This work investigates the function and regulatory principle of IRF2-INPP4B signaling in the progression of AML.
Materials and Methods: CD4+ T-cells were extracted from peripheral blood and characterized via flow cytometry. Flow cytometry was used to estimate apoptosis in the HL60 AML cell line and determine the Th1/Th2 cell ratio. Quantitative real-time polymerase chain reaction was used to measure IRF2 mRNA. Western blotting was performed to evaluate the protein levels of IRF2, INPP4B, JAK2, p-JAK2, STAT3, p-STAT3, and caspase 3. Interleukin-4 and interferon gamma concentrations were determined using enzyme-linked immunoadsorption assay kits.
Results: We discovered that levels of IRF2 and INPP4B were high in AML-derived CD4+ T-cells. Furthermore, CD4+ T-cells encouraged HL60 cell apoptosis. Downregulation of IRF2 encouraged HL60 cell apoptosis via alterations in the Th1/Th2 ratio while the overexpression of IRF2 stimulated the JAK2-STAT3 signaling channel and downregulated caspase 3.
Conclusion: We revealed that IRF2-INPP4B signaling in CD4+ T-cells stimulated the JAK2-STAT3 signaling channel and downregulated caspase 3, reducing AML cell apoptosis and aggravating AML progression. This work highlights an important regulatory principle concerning AML progression, as the IRF2-INPP4B pathway might impact the JAK2-STAT3 signaling channel. The findings contribute to our knowledge of the complicated interplay of these pathways in AML.

Keywords: Acute myeloid leukemia, Apoptosis, IRF2-INPP4B, JAK2-STAT3 signaling channel

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IRF2-INPP4B Yolağı Akut Miyeloid Lösemide Olumsuz Etkilidir

Xiangqin Xing¹, Mei Zhang¹, Shengfen Tan¹, Junfeng Zhu², Jiajia Li², Pingping Zhang², Yuan Yuan², Meng Wang¹, Feng Zhang^1
1Bengbu Medical University, Department of Hematology, Bengbu, P.R. China
²The First Affiliated Hospital of Bengbu Medical University, Department of Hematology, Bengbu, P.R. China

Amaç: İnterferon düzenleyici faktör 2 (IRF2) ve inositol polifosfat 4-fosfataz B (INPP4B), bağışıklık T-hücrelerinin farklılaşmasında kritik rol oynar. Ancak, IRF2-INPP4B sinyal yolunun akut miyeloid lösemi (AML) hücrelerinin apoptozundaki düzenleyici mekanizması net değildir. Bu çalışma, IRF2-INPP4B sinyalinin AML ilerlemesindeki işlevini ve düzenleyici prensiplerini araştırmaktadır.
Gereç ve Yöntem: Periferik kandan izole edilen CD4+ T-hücreleri akım sitometri ile tanımlandı. HL60 AML hücre hattında apoptozun hesaplanması ve Th1/Th2 hücre oranı belirlenmesi için akım sitometrisi kullanıldı. IRF2 mRNA ölçümü kantitatif gerçek zamanlı polimeraz zincir reaksiyonu ile yapıldı. IRF2, INPP4B, JAK2, p-JAK2, STAT3, p-STAT3 ve kaspaz 3 protein düzeyleri, Western blot ile değerlendirildi. İnterlökin-4 ve interferon gama konsantrasyonları ELISA kitleri ile ölçüldü.
Bulgular: AML kaynaklı CD4+ T-hücrelerinde IRF2 ve INPP4B seviyeleri yüksek bulundu. Ayrıca, CD4+ T-hücreleri, HL60 hücre apoptozunu artırdı. IRF2 baskılanması, Th1/Th2 oranını değiştirerek HL60 hücre apoptozunu artırırken IRF2 ifadesindeki artış, JAK2-STAT3 sinyal yolunu aktive etti ve kaspaz 3’ü baskıladı.
Sonuç: IRF2-INPP4B sinyal yolu, CD4+ T-hücrelerinde JAK2-STAT3 yolunu aktive ederek kaspaz 3’ü baskılar ve AML hücre apoptozunu engelleyerek AML ilerlemesini artırır. Bu çalışma, AML ilerlemesinde IRF2-INPP4B yolunun önemini ortaya koymakta ve JAK2-STAT3 sinyalizasyonu ile olan etkileşimini vurgulamaktadır. Bulgular, AML’deki bu karmaşık moleküler mekanizmaların anlaşılmasına katkı sağlamaktadır.

Anahtar Kelimeler: Akut miyeloid lösemi, Apoptoz, IRF2-INPP4B, JAK2-STAT3 sinyal yolu

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