Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2-dependent adult T-cell leukemia.

Therapeutic Approaches

Abstract

Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokine-dependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.

Authors

Zhang, Meili; Mathews Griner, Lesley A; Ju, Wei; Duveau, Damien; Guha, Rajarshi; Petrus, Michael N; Wen, Bernard; Maeda, Michiyuki; Shinn, Paul; Ferrer-Alegre, Marc; Conlon, Kevin D; Bamford, Richard N; O'Shea, John J; Thomas, Craig; Waldmann, Thomas A;

Keywords

  • Aniline Compounds/ pharmacology
  • Animals
  • Antineoplastic Agents/ pharmacology
  • Apoptosis/ drug effects
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Humans
  • Interleukin Receptor Common gamma Subunit/ deficiency
  • Interleukin Receptor Common gamma Subunit/ genetics
  • Interleukin-2/ metabolism
  • Janus Kinases/ antagonists & inhibitors
  • Janus Kinases/ metabolism
  • Leukemia-Lymphoma, Adult T-Cell/ drug therapy
  • Leukemia-Lymphoma, Adult T-Cell/ metabolism
  • Leukemia-Lymphoma, Adult T-Cell/ pathology
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Pyrazoles/ pharmacology
  • STAT Transcription Factors/ antagonists & inhibitors
  • STAT Transcription Factors/ metabolism
  • Signal Transduction/ drug effects
  • Sulfonamides/ pharmacology
  • Xenograft Model Antitumor Assays
  • bcl-X Protein/ antagonists & inhibitors
  • bcl-X Protein/ metabolism

External Links