Role of the STAT1 pathway in apoptosis induced by fludarabine and JAK kinase inhibitors in B-cell chronic lymphocytic leukemia

• Published in: Leukemia & lymphoma Vol. 46; no. 3; pp. 435 - 442
• Main Authors: Martinez-Lostao, Luis, Briones, Javier, Forné, Ignasi, Martinez-Gallo, Monica, Ferrer, Beatriz, Sierra, Jordi, Rodriguez-Sanchez, Jose Luis, Juarez, Candido
• Format: Journal Article
• Language: English
• Published: United States Informa UK Ltd 01.03.2005; Taylor & Francis
• Subjects: AG490; Aged; Aged, 80 and over; apoptosis; Apoptosis - drug effects; B-CLL; Cell Survival - drug effects; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - physiology; Electrophoretic Mobility Shift Assay; Female; Flow Cytometry; fludarabine; Humans; Interferon-gamma - pharmacology; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Male; Middle Aged; Protein-Tyrosine Kinases - antagonists & inhibitors; Quinazolines - pharmacology; Signal Transduction - drug effects; Signal Transduction - physiology; STAT1; STAT1 Transcription Factor; Time Factors; Trans-Activators - antagonists & inhibitors; Trans-Activators - physiology; Tumor Cells, Cultured; Tyrphostins - pharmacology; Vidarabine - analogs & derivatives; Vidarabine - pharmacology; WHI-P131
• ISSN: 1042-8194; 1029-2403
• DOI: 10.1080/10428190400018398

Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors that have been implicated in tumoral transformation, especially in hematological malignancies. Because of this, the JAK/STAT pathway is attractive as a therapeutic target in these tumors. In the present study, we analyzed the ability of fludarabine and two JAK kinase inhibitors, AG490 and WHI-P131, to block STAT1 activation and induce apoptosis on B-cell chronic lymphocytic leukemia (B-CLL) cells. All drugs were able to induce a high percentage of apoptosis on B-CLL cells from all patients studied. However, only AG490 and WHI-P131 were able to strongly suppress the STAT1 activation of B-CLL cells. In conclusion, our data show that JAK kinase inhibitors, such as AG490 and WHI-P131 are able to inhibit the STAT1 pathway on B-CLL cells and are strong inductors of apoptosis on these cells.