Targeting STAT5 or STAT5-Regulated Pathways Suppresses Leukemogenesis of Ph+ Acute Lymphoblastic Leukemia.

Abstract

Combining standard cytotoxic chemotherapy with BCR-ABL1 tyrosine kinase inhibitors (TKI) has greatly improved the upfront treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, due to the development of drug resistance through both BCR-ABL1-dependent and -independent mechanisms, prognosis remains poor. The STAT5 transcription factor is activated by BCR-ABL1 and by JAK2-dependent cytokine signaling; therefore, inhibiting its activity could address both mechanisms of resistance in Ph+ ALL. We show here that genetic and pharmacologic inhibition of STAT5 activity suppresses cell growth, induces apoptosis, and inhibits leukemogenesis of Ph+ cell lines and patient-derived newly diagnosed and relapsed/TKI-resistant Ph+ ALL cells ex vivo and in mouse models. STAT5 silencing decreased expression of the growth-promoting PIM-1 kinase, the apoptosis inhibitors MCL1 and BCL2, and increased expression of proapoptotic BIM protein. The resulting apoptosis of STAT5-silenced Ph+ BV173 cells was rescued by silencing of BIM or restoration of BCL2 expression. Treatment of Ph+ ALL cells, including samples from relapsed/refractory patients, with the PIM kinase inhibitor AZD1208 and/or the BCL2 family antagonist Sabutoclax markedly suppressed cell growth and leukemogenesis ex vivo and in mice. Together, these studies indicate that targeting STAT5 or STAT5-regulated pathways may provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease.Significance: Suppression of STAT5 by BCL2 and PIM kinase inhibitors reduces leukemia burden in mice and constitutes a new potential therapeutic approach against Ph+ ALL, especially in tyrosine kinase inhibitor-resistant disease. Cancer Res; 78(20); 5793-807. ©2018 AACR.

• Authors: Valentina Minieri, Marco De Dominici, Patrizia Porazzi, Samanta A Mariani, Orietta Spinelli, Alessandro Rambaldi, Luke F Peterson, Pierluigi Porcu, Marja T Nevalainen, Bruno Calabretta
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 20 Pg. 5793-5807 (10 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 30154155 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• BCL2 protein, human
• Cytokines
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• STAT5 Transcription Factor
• STAT5A protein, human
• Tumor Suppressor Proteins
• Fusion Proteins, bcr-abl

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Cell Survival
• Cytokines
• Disease Progression
• Drug Resistance, Neoplasm
• Fusion Proteins, bcr-abl (metabolism)
• Gene Expression Regulation, Leukemic
• Gene Silencing
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Mice
• Molecular Targeted Therapy
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Neoplasm Recurrence, Local
• Neoplasm Transplantation
• Philadelphia Chromosome
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (pathology, therapy)
• Prognosis
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• RNA, Small Interfering (metabolism)
• STAT5 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics, metabolism)