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EnglishCombining standard cytotoxic chemotherapy with BCRABL1 tyrosine kinase inhibitors (TKI) has greatly improved the upfront treatment of patients with Philadelphia chromosomepositive (Ph+) acute lymphoblastic leukemia (ALL). However, due to the development of drug resistance through both BCRABL1- 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/TKIresistant Ph+ ALL cells ex vivo and in mouse models. STAT5 silencing decreased expression of the growth-promoting PIM-1 kinase, the apoptosis inhibitorsMCL1 and BCL2, and increased expression of proapoptotic BIMprotein. 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 pathwaysmay provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease.
| Titolo: | Targeting STAT5 or STAT5-regulated pathways suppresses leukemogenesis of Ph+ acute lymphoblastic leukemia |
| Autori: | |
| Parole Chiave: | Oncology; Cancer Research |
| Settore Scientifico Disciplinare: | Settore MED/15 - Malattie del Sangue |
| Data di pubblicazione: | 15-ott-2018 |
| Rivista: | |
| Tipologia: | Article (author) |
| Data ahead of print / Data di stampa: | 28-ago-2018 |
| Digital Object Identifier (DOI): | 10.1158/0008-5472.CAN-18-0195 |
| Appare nelle tipologie: | 01 - Articolo su periodico |
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