MLL undergoes multiple distinct chromosomal translocations to yield aggressive leukemia with dismal outcomes. Besides their well-established role in leukemogenesis, MLL fusions also possess latent tumor-suppressive activity, which can be exploited as effective cancer treatment strategies using pharmacological means such as proteasome inhibitors (PIs). Here, using MLL-rearranged xenografts and MLL leukemic cells as models, we show that wild-type MLL is indispensable for the latent tumor-suppressive activity of MLL fusions. MLL dysfunction, shown as loss of the chromatin accumulation and subsequent degradation of MLL, compromises the latent tumor suppression of MLL-AF4 and is instrumental for the acquired PI resistance. Mechanistically, MLL dysfunction is caused by chronic PI treatment-induced epigenetic reprogramming through the H2Bub-ASH2L-MLL axis and can be specifically restored by histone deacetylase (HDAC) inhibitors, which induce histone acetylation and recruits MLL on chromatin to promote cell cycle gene expression. Our findings not only demonstrate the mechanism underlying the inevitable acquisition of PI resistance in MLL leukemic cells, but also illustrate that preventing the emergence of PI-resistant cells constitutes a novel rationale for combination therapy with PIs and HDAC inhibitors in MLL leukemias.
NOTCH1 mutations occur in approximately 10% of patients with chronic lymphocytic leukemia (CLL). However, the relationship between the genetic aberrations and tumor cell drug resistance or disease progression remains unclear. Frameshift deletions were detected by gene sequencing in the NOTCH1 PEST domain in three naive CLL patients. These mutations were associated with chromosomal abnormalities including trisomy 12 or 13q deletion. Of note, one of the patients developed Richter’s transformation during FCR treatment. Immunofluorescent and western blot analyses revealed a markedly higher intracellular domain of NOTCH (ICN) expression in the mutated cells compared with their unmutated counterparts and normal CD19+ B lymphocytes (P<0.01 and P<0.001, respectively). In addition, strong DNA-κB binding activities were observed in the mutant cells by gel shift assays. RT-PCR analysis revealed elevated RelA mRNA expression in the mutant cells, while RelB levels were variable. Reduced levels of RelA and RelB mRNA were observed in unmutated CLL and normal B cells. Compared to unmutated CLL and normal B cells, increased apoptosis occurred in the mutant cells in the presence of GSI (ICN inhibitor) and PDTC (NF-κB inhibitor), particularly under the synergistic effects of the two drugs (P=0.03). Moreover, IKKα and IKKβ, the active components in the NF-κB pathway, were markedly inhibited following prolonged treatment with GSI and PDTC. These results suggested that NOTCH1 mutations constitutively activate the NF-κB signaling pathway in CLL, which is likely related to ICN overexpression, indicating NOTCH1 and NF-κB as potential therapeutic targets in the treatment of CLL.
Background Resistance to proteasome inhibitors (PIs) is a major obstacle to the successful treatment of multiple myeloma (MM). Many mechanisms have been proposed for PI resistance; however, our mechanistic understanding of how PI resistance is inevitably acquired and reversed remains incomplete. Methods MM patients after bortezomib relapse, MM cell lines and mouse models were used to generate matched resistant and reversed cells. RNA sequencing and bioinformatics analyses were employed to assess dysregulated epigenetic regulators. In vitro and in vivo procedures were used to characterise PI-tolerant cells and therapeutic efficacy. Results Upon PI treatment, MM cells enter a slow-cycling and reversible drug-tolerant state. This reversible phenotype is associated with epigenetic plasticity, which involves tolerance rather than persistence in patients with relapsed MM. Combination treatment with histone deacetylase inhibitors and high-dosage intermittent therapy, as opposed to sustained PI monotherapy, can be more effective in treating MM by preventing the emergence of PI-tolerant cells. The therapeutic basis is the reversal of dysregulated epigenetic regulators in MM patients. Conclusions We propose an alternative non-mutational PI resistance mechanism that explains why PI relapse is inevitable and why patients regain sensitivity after a ‘drug holiday’. Our study also suggests strategies for epigenetic elimination of drug-tolerant cells.
Emerging evidence suggests that the three tyrosine kinase inhibitors currently approved for the treatment of patients with chronic myelogenous leukemia (CML) – imatinib, dasatinib, and nilotinib – have potential cardiotoxic effects. The mechanisms behind these events, and the relations between them, are largely unclear. For example, relative to dasatinib and nilotinib, severe congestive heart failure and left ventricular dysfunction are rare but prominent with imatinib treatment, particularly in patients receiving higher doses (>600 mg/day). In comparison with imatinib, prolongation of the QT interval is relatively common in patients treated with either dasatinib or nilotinib. In contrast to nilotinib, pericardial effusions are observed with both imatinib and dasatinib. It is suggested that these data, an evaluation of cardiac status, use of concomitant medications, and potential risk factors should be considered in the management of CML.
Chronic lymphocytic leukemia (CLL) is characterized by high heterogeneity in clinical features and outcomes in Western countries and China. In this study, the clinical and laboratory data of 210 CLL patients who were admitted to a single center in China between 2002 and 2011 were retrospectively analyzed. CLL patients had a median age of 60.2 years (range, 35–92 years) and CLL occurred more often in elderly female patients than in male patients (female:male, 1.2:1). The overall response rate [ORR, complete remission (CR) + partial remission (PR)] in the entire cohort of patients was 69.5% and the median overall survival (OS) was 67 months (95% CI, 57.88–76.11). In univariate analysis, an age of >60 years, chromosome 17p deletion (17p−) and elevated β2-MG were associated with a worse OS. Patients with all three poor prognostic factors had a worse outcome than patients with only one or two factors. Patients with 17p− had a significantly lower ORR (P=0.008) and shorter OS (P=0.001) than those without 17p−. Rituximab (R)-based treatment was able to overcome the poor prognosis associated with 17p−. Moreover, the addition of R to fludarabine (F) and cyclophosphamide (C) treatment significantly improved the OS (P=0.012) compared with FC alone in younger patients. However, there were no significant benefits for older patients (P=0.07). This implies that the age of a patient is important in their response to therapy and survival.
Indolent lymphoma (IL), the second most common lymphoma, remains incurable with chemotherapy alone. While R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) remains the standard frontline regimen for diffuse Large B –cell lymphoma, the optimal chemotherapy regimen for frontline therapy of advanced IL remains uncertain. FCR (fludarabine, cyclophosphamide, rituximab) has been shown to be better than fludarabine alone and fludarabine plus cyclophosphamide for IL. In FOLL05 trial, R-CHOP was compared with R-CVP (cyclophosphamide, vincristine, prednisone) and R-FM (fludarabine, mitoxantrone). The study showed that R-CHOP appears to have the best risk-benefit ratio for IL. The StiL NHL1 trial showed that BR (bendamustine, rituximab) has longer progression free survival and is better tolerated than R-CHOP. Long-term complications with secondary malignancies between the two regimens appear to be comparable. In this review, new combination regimens reported at 2012 ASCO annual meeting were evaluated for frontline and salvage therapy of indolent lymphoma.
Chronic lymphocytic leukemia (CLL) is one of the most often diagnosed hematological malignant tumors in the Western world and a type of inert B-cell lymphoma that commonly attacks the elderly. Small ubiquitin related modifier (SUMO)-specific protease 2 (SENP2) can act as a suppressor in various types of cancer by regulating the stability of β-catenin to affect the Notch signaling pathway; however, it has a low expression level in CLL cells. In this study, we firstly used western blot analysis and RT-qPCR to detect the protein and mRNA expression levels of SENP2 in the peripheral blood of patients with CLL and healthy volunteers. Secondly, we overexpressed or knocked down the expression of SENP2 in CLL cells and then determined the cell invasive and chemotactic ability in a Transwell assay and chemotaxis assay. We examined the sensitivity of the cells to cytarabine and dexamethasone via a CCK-8 assay and determined the cell apoptotic condition and the expression of the Notch signaling pathway using flow cytometry and western blot analysis. The results demonstrated that the patients with CLL had relatively low expression levels of SENP2. The overexpression of SENP2 in the CLL cells decreased their invasive and proliferative ability, as well as their chemotactic response and enhanced their sensitivity to cytarabine and dexamethasone, while it promoted cell apoptosis. The silencing of SENP2 in the CLL cells generally produced the opposite results. We thus hypothesized that the overexpression of SENP2 downregulated β-catenin expression, thus inhibiting the Notch signaling pathway in CLL cells. Moreover, the nuclear factor (NF)-κB signaling pathway was also regulated by the overexpression of SENP2. On the whole, the findings of this study indicate tha SENP2 can act as a tumor suppressor in CLL cells, and may thus prove to be a novel target for CLL treatment in clinical practice.
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