High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia

Abstract

In BCR-ABL1 ؉ leukemia, drug resistance is often associated with up-regulation of BCR-ABL1 or multidrug transporters as well as BCR-ABL1 mutations. Here we show that the expression level of the transcription factor STAT5 is another parameter that determines the sensitivity of BCR-ABL1 ؉ cells against tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, or dasatinib. Abelson-transformed cells, expressing high levels of STAT5, were found to be significantly less sensitive to TKI-induced apoptosis in vitro and in vivo but not to other cytotoxic drugs, such as hydroxyurea, interferon-␤, or Aca-dC. The STAT5-mediated protection requires tyrosine phosphorylation of STAT5 independent of JAK2 and transcriptional activity. In support of this concept, under imatinib treatment and with disease progression, STAT5 mRNA and protein levels increased in patients with Ph ؉ chronic myeloid leukemia. Based on our data, we propose a model in which disease progression in BCR-ABL1 ؉ leukemia leads to up-regulated STAT5 expression. This may be in part the result of clonal selection of cells with high STAT5 levels. STAT5 then accounts for the resistance against TKIs, thereby explaining the dose escalation frequently required in patients reaching accelerated phase. It also suggests that STAT5 may serve as an attractive target to overcome imatinib resistance in BCR-ABL1 ؉ leukemia. IntroductionMore than 99% of all patients with chronic myeloid leukemia (CML) and approximately 30% of acute lymphoid leukemia are characterized by the t(9;22)(q34;q11) translocation and the Philadelphia chromosome. Two chimeric oncogenic tyrosine kinase products, p185 BCR-ABL1 or p210 BCR-ABL1 , may be generated. 1,2 Whereas p210 BCR-ABL1 is associated with CML, p185 BCR-ABL1 is almost exclusively found in acute lymphoid leukemia. 3 The BCR-ABL1 oncoprotein promotes leukemia development by activating multiple signal transduction pathways that regulate cell proliferation, transformation, and survival. BCR-ABL1-induced acute lymphoid leukemia is characterized by an excess of lymphoblasts and progresses rapidly, whereas BCR-ABL1 ϩ CML is a stem cell-derived disease with distinct phases: chronic phase (CP), which may last for several years, accelerated phase (AP), and blast crisis (BC). 4 Therapy of BCR-ABL1-induced diseases was significantly improved by the development of small molecular weight inhibitors blocking the activity of the ABL1 kinase. Imatinib was the first substance, soon followed by other kinase inhibitors (TKIs), such as dasatinib and nilotinib. [5][6][7] All these TKIs target the enzymatic activity of the ABL1 tyrosine kinases. 6,8,9 Imatinib is now the standard first-line therapy for all CML patients. However, not all CML patients respond equally well. 10 Moreover, approximately 15% to 25% of the patients who initially responded well acquire resistance against imatinib during therapy. The percentage of nonresponders is even higher in AP. [10][11][12] These patients are treated with increased imatinib dosage (600-800 mg/day), secondge...

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

“…8 Moreover, during disease progression, the levels of STAT5 mRNA and protein increase, and STAT5 production and activation is triggered not only by BCR-ABL1 or mutant KIT, but also by other pro-oncogenic pathways relevant to disease progression and resistance. 9 Taken together, these observations strongly suggest that STAT5 and AKT are key drivers in drug-resistant CML and SM, and thus represent potential therapeutic targets. Small molecules targeting STAT5 or AKT may indeed be effective in these malignancies, especially in TKIs-resistant patients.…”

“…9,48 However, mutations in the kinase domain of BCR-ABL1 are thought to be a primary cause of resistance in patients with CML, seen in up to 40-60% of cases of secondary resistance.…”

Combination of Imatinib with CXCR4 Antagonist BKT140 Overcomes the Protective Effect of Stroma and Targets CML In Vitro and In Vivo

“…Mitogen-activated protein kinase, phosphoinositide 3-kinase, and JAK-STAT signaling are known to be involved in BCR-ABL-independent TKI resistance and represent targeting opportunities in CML (38). For example, STAT5 was shown to mediate imatinib resistance and was upregulated in leukemic cells from imatinib-resistant patients (39). Similarly, CML cell lines cultured with HS5 stromal cells were protected from imatinib-induced apoptosis by STAT3 upregulation (40).…”

STAT5a-targeting miRNA enhances chemosensitivity to cisplatin and 5-fluorouracil in human colorectal cancer cells

“…Other studies have shown that STAT5 regulated the sensitivity of cancer cells to chemotherapy. Researchers found that high STAT5 levels mediate imatinib resistance in chronic myeloid leukemia (CML) (25); inhibition of STAT5 by siRNA significantly reduced the activities of multi-drug resistant protein and enhanced the sensitivity of CML cells to imatinib (26). Research on squamous cell carcinoma of the head and neck demonstrated that STAT5 activation was associated with resistance to cisplatinmediated apoptosis and growth inhibition induced by the epidermal growth factor receptor tyrosine kinase inhibitor, such as erlotinib (27).…”