title: Differential contributions of STAT5A and STAT5B to stress protection and tyrosine kinase inhibitor resistance of chronic myeloid leukemia stem/progenitor cells.
abstract: STAT5 fulfills essential roles in hematopoietic stem cell (HSC) self-renewal and chronic myeloid leukemia (CML), a prototypical stem cell malignancy. However, the specific contributions of the two related genes STAT5A and STAT5B have not been determined. In this study, we used a RNAi-based strategy to establish participation of these genes to CML disease and persistence following targeted therapy. We showed that STAT5A/STAT5B double-knockdown triggers CML cell apoptosis and suppresses both normal and CML HSC long-term clonogenic potential. STAT5A and STAT5B exhibited similar prosurvival activity, but STAT5A attenuation alone was ineffective at impairing growth of normal and CML CD34(+) cells isolated at diagnosis. In contrast, STAT5A attenuation was sufficient to enhance basal oxidative stress and DNA damage of normal CD34(+) and CML cells. Furthermore, it weakened the ability to manage exogenous oxidative stress, increased p53 (TRP53)/CHK-2 (CHEK2) stress pathway activation, and enhanced prolyl hydroxylase domain (PHD)-3 (EGLN3) mRNA expression. Only STAT5A and its transactivation domain-deficient mutant STAT5AΔ749 specifically rescued these activities. STAT5A attenuation was also active at inhibiting growth of CML CD34(+) cells from patients with acquired resistance to imatinib. Our findings show that STAT5A has a selective role in contributing to stress resistance through unconventional mechanisms, offering new opportunities to eradicate the most primitive and tyrosine kinase inhibitor-resistant CML cells with an additional potential to eradicate persistent stem cell populations.
authors: Inserm U1016, Institut Cochin, Paris, France.
authors: Luana
authors: L
authors: Casetti
authors: Séverine
authors: S
authors: Martin-Lannerée
authors: Imen
authors: I
authors: Najjar
authors: Isabelle
authors: I
authors: Plo
authors: Sylvie
authors: S
authors: Augé
authors: Lydia
authors: L
authors: Roy
authors: Jean-Claude
authors: JC
authors: Chomel
authors: Evelyne
authors: E
authors: Lauret
authors: Ali G
authors: AG
authors: Turhan
authors: Isabelle
authors: I
authors: Dusanter-Fourt
mesh_terms: D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005455:Fluorescent Antibody Technique; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D025521:Tumor Suppressor Proteins; D000068877:Imatinib Mesylate; D006861:Hydrogen Peroxide