Abstract
Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). Unfortunately, some patients are resistant primarily to imatinib and others develop drug resistance, prompting interest in the discovery of new drug targets. Although much of this resistance can be explained by the presence of mutations within the tyrosine kinase domain of BCR-ABL, such mutations are not universally identified. Interferon regulatory factor-8 (IRF-8) is a transcription factor that is essential for myelopoiesis. Depressed IRF-8 levels are observed in a majority of CML patients and Irf-8(-/-) mice exhibit a CML-like disease. The underlying mechanisms of IRF-8 loss in CML are unknown. We hypothesized that BCR-ABL suppresses transcription of IRF-8 through STAT5, a proximal BCR-ABL target. Treatment of primary cells from newly diagnosed CML patients in chronic phase as well as BCR-ABL(+) cell lines with imatinib increased IRF-8 transcription. Furthermore, IRF-8 expression in cell line models was necessary for imatinib-induced antitumor responses. We have demonstrated that IRF-8 is a direct target of STAT5 and that silencing of STAT5 induced IRF-8 expression. Conversely, activating STAT5 suppressed IRF-8 transcription. Finally, we showed that STAT5 blockade using a recently discovered antagonist increased IRF-8 expression in patient samples. These data reveal a previously unrecognized BCR-ABL-STAT5-IRF-8 network, which widens the repertoire of potentially new anti-CML targets.
Highlights
The Interferon regulatory factor-8 (IRF-8) tumor suppressor gene is down-regulated in chronic myeloid leukemia (CML)
In six of eight patient samples, we observed a significant increase in IRF-8 mRNA levels in samples treated with imatinib compared with vehicle (Fig. 1A)
The IRF-8 transcription factor has long been appreciated as a tumor suppressor in CML
Summary
The IRF-8 tumor suppressor gene is down-regulated in chronic myeloid leukemia (CML). Results: The STAT5 transcription factor regulates IRF-8 expression in CML cells. Significance: An oncogene driven STAT5-IRF-8 signaling axis regulates CML biology and may be implicated in other types of myeloid malignanices Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). We showed that STAT5 blockade using a recently discovered antagonist increased IRF-8 expression in patient samples These data reveal a previously unrecognized BCR-ABL-STAT5-IRF-8 network, which widens the repertoire of potentially new anti-CML targets. IRF-8 levels were rapidly restored in patients who achieved complete cytogenetic remission in response to IFN-␣-based therapy [22] These observations implicate IRF-8 as a tumor suppressor gene for leukemogenesis in CML. Our data support a new model whereby BCR-ABL induces STAT5 activation, which enables STAT5 to partner directly with IRF-8 to repress its transcription, thereby losing its potential tumor suppressor capability. Our results provide a novel explanation for the longstanding conundrum of why IRF-8 levels are absent or strongly depressed in patients with CML
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