Abstract
Chronic myeloid leukemia (CML) is a clonal malignant disease caused by the expression of BCR/ABL. MDM2 (human homolog of the murine double minute-2) inhibitors such as Nutlin-3 have been shown to induce apoptosis in a p53-dependent manner in CML cells and sensitize cells to Imatinib. Here, we demonstrate that JNJ-26854165, an inhibitor of MDM2, inhibits proliferation and triggers cell death in a p53-independent manner in various BCR/ABL-expressing cells, which include primary leukemic cells from patients with CML blast crisis and cells expressing the Imatinib-resistant T315I BCR/ABL mutant. The response to JNJ-26854165 is associated with the downregulation of BCR/ABL dependently of proteosome activation. Moreover, in all tested CML cells, with the exception of T315I mutation cells, combining JNJ-26854165 and tyrosine kinase inhibitor (TKI) Imatinib or PD180970 leads to a synergistic effect. In conclusion, our results suggest that JNJ-26854165, used either alone or in combination with TKIs, represents a promising novel targeted approach to overcome TKI resistance and improve patient outcome in CML.
Highlights
Chronic myeloid leukemia (CML) is a clonal malignant disease hallmarked by the expression of the BCR/ABL fusion protein that results from a reciprocal translocation involving chromosomes 9 and 22
We first examined the antiproliferation effect of JNJ-165 on primary cells from 24 newly diagnosed patients with CML, 9 patients with CML-accelerated phase (AP)/blast-crisis phase (BC), and 13 cases with CML-CP treated with Imatinib or dasatinib, in whom expression of BCR/ABL mRNA determined by real time RT-PCR was very low or undetectable
CML primary cells were exposed to 2 μM JNJ-165 for 72 hours, the viability of cells from the CML-CP patients with BCR/ABL positive and CML AP/BP patients was reduced by 32.9% and 23.4%, respectively, compared with cells from the patients with very low or undetectable BCR/ABL (Figure 1A)
Summary
Chronic myeloid leukemia (CML) is a clonal malignant disease hallmarked by the expression of the BCR/ABL fusion protein that results from a reciprocal translocation involving chromosomes 9 and 22. BCR/ ABL possesses a deregulated tyrosine kinase activity that drives a number of downstream signaling pathways, confers survival and proliferation advantages and restrains apoptosis, contributing to the pathogenesis of CML [1]. A small molecule tyrosine kinase inhibitor (TKI) that competitively binds to the ATP-binding site of BCR/ABL, is currently considered a first-line agent for the treatment of patients with newly diagnosed chronic-phase (CP) CML [2, 4]. All agents aimed at targeting the ATP-binding pocket of the BCR/ABL kinase domain alone do not eliminate CML stem cells [10,11,12]
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