Abstract
Abstract Complete eradication of CML has not been possible in patients because of the presence of minimal residual disease (MRD) in sanctuary sites like the bone marrow (BM). One of the reasons for MRD is the milieu of cytokines and growth factors present in the BM microenvironment, that contribute to BCR-ABL independent drug resistance in CML. For example, in the present study, we demonstrate the importance of STAT3-mediated drug resistance in the BM microenvironment by showing that conditioned media (CM) derived from both normal and patient-derived mesenchymal stem cells and osteoblasts leads to STAT3 phosphorylation (pSTAT3-Y705) and concomitant drug resistance to Nilotinib in CML cells. Inhibiting the activity or reducing the expression of JAK2 and TYK2 was necessary for sensitizing cells to Nilotinib in CM. Moreover, increased pSTAT3-Y705 levels were associated with increased STAT3 transcriptional activity and up-regulation of Mcl-1 and cyclin D1. Our study indicates that there is an inherent redundancy in CM-mediated STAT3 activation pathway because concomitant neutralization of two potent activators of STAT3, IL-6 and G-CSF, does not reverse CM-mediated protection against Nilotinib. Furthermore, utilizing a SCID-hu bone implant in vivo model, we show that K562 cells with reduced STAT3 showed significantly lower tumor burden, which could be attributed to not only the slower proliferation rate, but also to the observation that these cells underwent cell death in BM stromal derived CM. Finally, CD34+ cells from CML patients when exposed to CM showed an increase in STAT3 phosphorylation which correlated with the development of de novo resistance to Nilotinib-mediated cell death. Taken together our data indicate that STAT3 is an important target in CML and its direct inhibition, along with BCR-ABL inhibitors, will likely be the most effective therapeutic strategy for reversing resistance within the BM microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5033. doi:10.1158/1538-7445.AM2011-5033
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