Proteasome inhibition in myelodysplastic syndromes and acute myelogenous leukemia cell lines
ABSTRACT In this work, effects of bortezomib on apoptosis, clonal progenitor growth, cytokine production, and NF-κB expression in patients with MDS with cytopenias requiring transfusion support are examined. Bortezomib increased apoptosis in marrow mononuclear cells but had no effects on CFU-GM, BFU-E, or CFU-L content. No consistent effects on NF-κB activation in vivo were noted. To further define the role of bortezomib in AML and MDS, we examined it in combination with several targeted agents and chemotherapeutic agents in vitro. Combinations with arsenic trioxide, sorafenib, and cytarabine demonstrated synergistic in vitro effects in AML cell lines.
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- "Studies have shown that haploinsufficiency of ribosomal protein genes causes selective activation of TP53 (p53) in human erythroid progenitor cells (Dutt et al, 2011). The positive enrichment of the proteasome has been reported only in high risk MDS, and often associated with apoptosis after treatment with proteasome inhibitors (Alimena et al, 2011; Liesveld et al, 2011). "
ABSTRACT: Refractory anaemia with ring sideroblasts (RARS) is distinguished by hyperplastic inefficient erythropoiesis, aberrant mitochondrial ferritin accumulation and anaemia. Heterozygous mutations in the spliceosome gene SF3B1 are found in a majority of RARS cases. To explore the link between SF3B1 mutations and anaemia, we studied mutated RARS CD34(+) marrow cells with regard to transcriptome sequencing, splice patterns and mutational allele burden during erythroid differentiation. Transcriptome profiling during early erythroid differentiation revealed a marked up-regulation of genes involved in haemoglobin synthesis and in the oxidative phosphorylation process, and down-regulation of mitochondrial ABC transporters compared to normal bone marrow. Moreover, mis-splicing of genes involved in transcription regulation, particularly haemoglobin synthesis, was confirmed, indicating a compromised haemoglobinization during RARS erythropoiesis. In order to define the phase during which erythroid maturation of SF3B1 mutated cells is most affected, we assessed allele burden during erythroid differentiation in vitro and in vivo and found that SF3B1 mutated erythroblasts showed stable expansion until late erythroblast stage but that terminal maturation to reticulocytes was significantly reduced. In conclusion, SF3B1 mutated RARS progenitors display impaired splicing with potential downstream consequences for genes of key importance for haemoglobin synthesis and terminal erythroid differentiation. © 2015 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.British Journal of Haematology 08/2015; DOI:10.1111/bjh.13610 · 4.96 Impact Factor
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- "The ORR was 56%, with 14 achieving hematologic improvement . Bortezomib is a proteasome and NF-kb inhibitor that can induce apoptosis in vitro in MDS/AML leukemia bone marrow cells  and has demonstrated benefit when used as a single agent in MDS patients . Bortezomib has been studied in combination with lenalidomide, low-dose cytarabine (LDAC) and the HDACi Belinostat in patients with AML and higher-risk MDS, though its benefit remains unclear [86e88]. "
ABSTRACT: The myelodysplastic syndromes (MDS) are a heterogenous collection of clonal hematopoietic malignancies that exist as a subgroup of the myeloid neoplasms as classified by the World Health Organization (WHO). They are characterized by ineffective hematopoiesis, subsequent cytopenias, transformation to acute myeloid leukemia (AML), and poor overall survival. There are currently three FDA-approved medications for MDS; lenalidomide, azacitidine, and decitabine. The role of these agents is to diminish the clinical impact of MDS and delay its progression to AML. However, despite known results with these monotherapies, recent clinical trials with a variety of combinations for MDS have demonstrated promising results. These trials include combinations of hypomethylating agents, histone deacetylase inhibitors, growth factors, and chemotherapy among others. In this paper we review the current literature on combination therapies in MDS, analyze on-going and concluded trials, and suggest future possibilities for combination strategies in MDS. Copyright © 2014 Elsevier Ltd. All rights reserved.Bailliè re s Best Practice and Research in Clinical Haematology 11/2014; 28(1). DOI:10.1016/j.beha.2014.11.002 · 2.55 Impact Factor
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ABSTRACT: Abstract The 5q deletion is a chromosomal abnormality that is observed in a subset of myelodysplastic syndromes (MDS). When isolated, this abnormality defines a specific clinical syndrome termed MDS associated with isolated deletion 5q, presenting with macrocytic anemia, normal platelet count or slight thrombocytosis, hypolobated megakaryocytes and fewer than 5% blasts in the bone marrow. MDS with the 5q deletion have a particular sensitivity to treatment with lenalidomide, a thalidomide analog. In this article, molecular changes in 5q- MDS derived from haploinsufficiency of genes encoded from the deleted region in 5q are reviewed, and mechanisms that link these molecular lesions with lenalidomide sensitivity are proposed.Leukemia & lymphoma 09/2011; 53(5):779-88. DOI:10.3109/10428194.2011.623255 · 2.89 Impact Factor