Combining 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.
Targeting STAT5 or STAT5-regulated pathways suppresses leukemogenesis of Ph+ acute lymphoblastic leukemia / V. Minieri, M. De Dominici, P. Porazzi, S.A. Mariani, O. Spinelli, A. Rambaldi, L.F. Peterson, P. Porcu, M.T. Nevalainen, B. Calabretta. - In: CANCER RESEARCH. - ISSN 0008-5472. - 78:20(2018 Oct 15), pp. 5793-5807.
|Titolo:||Targeting STAT5 or STAT5-regulated pathways suppresses leukemogenesis of Ph+ acute lymphoblastic leukemia|
|Parole Chiave:||Oncology; Cancer Research|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||15-ott-2018|
|Data ahead of print / Data di stampa:||28-ago-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1158/0008-5472.CAN-18-0195|
|Appare nelle tipologie:||01 - Articolo su periodico|