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.
"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). "
"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]. "
[Show abstract][Hide abstract] 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.
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