Abstract
Adult T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis. Although it has been found that activation of Notch1 signaling occurs in >50% T-ALL patients, γ-secretase inhibitors that target Notch1 signaling are of limited efficacy. However, c-Myc is an important direct target of Notch1 and, thus, c-Myc is another potential therapeutic target for T-ALL. Valproic acid (VPA), a histone deacetylase inhibitor, has been reported to treat various hematological malignancies. In the present study, we showed that c-Myc expression, at a transcriptional level, was dose-dependently downregulated in VPA-induced growth inhibition in T-ALL cell lines, Jurkat and CCRF-CEM cells. 10058-F4, a small molecule c-Myc inhibitor, could increase the downregulation of c-Myc and markedly increase the growth inhibition and cell death induced by VPA in Jurkat and CCRF-CEM cells, which was accompanied by obvious cleavage of capase-3. Z-VAD-FMK, a caspase inhibitor, partially prevented the anti-leukemic effect. The results of the present study suggest that c-Myc inhibitors increase cell death induced by VPA in a caspase-dependent and -independent manner, and their combination could be a potent therapeutic strategy for adult T-ALL patients.
Highlights
T‐cell acute lymphoblastic leukemia (T‐ALL), an aggressive malignancy arising from T‐cell progenitors, accounts for ~15% of ALL cases in children and ~25% in adults
Western blots revealed that after Jurkat and CCRF‐CEM cells were treated with Valproic acid (VPA) at various concentrations for 24 h, the expression of c‐Myc protein was markedly downregulated in a dose‐dependent manner, and was accompanied by cleavage of caspase‐3 (Fig. 1A). Quantitative polymerase chain reaction (qPCR) was performed to measure the c‐Myc mRNA levels, and it was found that the expression of c‐Myc was decreased in Jurkat and CCRF‐CEM cells treated with 0.8 mM VPA for 24 h (Fig. 1B; P
The western blotting results showed that c‐Myc expression levels in Jurkat and CCRF‐CEM cells treated with VPA (0, 0.8 and 1.6 mM) combined with 60 μM 10058‐F4 decreased further compared with the corresponding controls (Fig. 2)
Summary
T‐cell acute lymphoblastic leukemia (T‐ALL), an aggressive malignancy arising from T‐cell progenitors, accounts for ~15% of ALL cases in children and ~25% in adults. The HD mutation results in ligand‐independent proteolytic cleavage of Notch, while the PEST mutation blocks Fbw interaction with Notch and, thereby, prevents its polyubiquitination and degradation [3,4]. The mutations of these two domains result in constitutive activation of the Notch signaling pathway [1]. ~30% of T‐ALL patients harbor inactivating mutations of the Fbw gene, which activate Notch signaling [1]. It has been demonstrated that c‐Myc is a direct and important target gene of Notch, and its expression levels have been observed to increase along with activation of Notch signaling in T‐ALL [5]. C‐Myc may be a target for therapy in T‐ALL
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