Research progress on myelodysplastic syndromes:report of the 2011 annual meeting of American Society of Hematology / 白血病·淋巴瘤

Myelodysplastic syndromes (MDS) are a heterogenous group of hematologic malignancies characterized by clonal expansion of BM myeloid cells with impaired differentiation. Of particular interest mutations is the recent recognition that genes involved in the regulation of histone function (EZH2, ASXL1,and UTX) and DNA methylation (DNMT3A,IDH 1/IDH2,TET2) are recurrently mutated in MDS,providing an important link between genetic and epigenetic alterations in this disease. Ongoing analysis of the seminal AZA-001study has taught many important lessons in the use of DNA methyltransferase (DNMT) inhibitors.Improved survival in patients with high-risk MDS treated with azacitidine extends to patients with any International Working Group-defined hematologic response.New information on the impact of DNMT inhibitors on the immune system and on stem cells will likely lead to novel uses of these drugs in MDS and other hematologic and nonhematologic malignancies. The immunomodulating drug thalidomide and its derivative lenalidomide have been used in the treatment of MDS,principally in lower-risk MDS.

DNA Methylation Changes Following 5-azacitidine Treatment in Patients with Myelodysplastic Syndrome

DNA methyltransferase inhibitor, 5-azacitidine (AC) is effective in myelodysplastic syndromes (MDS) and can induce re-expression in cancer. We analyzed the methylation of 25 tumor suppressor genes in AC-treated MDS. Hypermethylation of CDKN2B, FHIT, ESR1, and IGSF4 gene was detected in 9/44 patients. In concordance with the clinical response, a lack of or decreased methylation in 4 patients with hematologic improvements and persistent methylation in 4 others with no response was observed. The mRNA expression of CDKN2B, IGSF4, and ESR1 was significantly reduced in MDS. Our results suggest that methylation changes contribute to disease pathogenesis and may serve as marker to monitor the efficacy of treatments.

Osteoblast differentiation of human bone marrow stromal cells (hBMSC) according to age for bone tissue engineering

Tissue engineered bone (TEB) can replace an autogenous bone graft requiring an secondary operation site as well as avoid complications like inflammation or infection from xenogenic or synthetic bone graft. Adult mesenchymal stem cells (MSC) for TEB are considered to have various ranges of differentiation capacity or multipotency by the donor site and age. This study examined the effect of age on proliferation capacity, differentiation capacity and bone morphogenetic protein-2 (BMP-2) responsiveness of human bone marrow stromal cells (hBMSC) according to the age. In addition, to evaluate the effect on enhancement for osteoblast differentiation, the hBMSC were treated with Trichostatin A (TSA) and 5-Azacitidine (5-AZC) which was HDAC inhibitors and methyltransferase inhibitors respectively affecting chromatin remodeling temporarily and reversibly. The young and old group of hBMSC obtained from the iliac crest from total 9 healthy patients, showed similar proliferation capacity. Cell surface markers such as CD34, CD45, CD90 and CD105 showed uniform expression regardless of age. However, the young group showed more prominent transdifferentiation capacity with adipogenic differentiation. The osteoblast differentiation capacity or BMP responsiveness was low and similar between young and old group. TSA and 5-AZC showed potential for enhancing the BMP effect on osteoblast differentiation by increasing the expression level of osteogenic master gene, such as DLX5, ALP. More study will be needed to determine the positive effect of the reversible function of HDAC inhibitors or methyltransferase inhibitors on enhancing the low osteoblast differentiation capacity of hBMSC.

New agents for the treatment of myelodysplastic syndromes / 대한내과학회지

Myelodysplastic syndromes (MDS) are a heterogenous group of clonal stem cell disorders commonly characterized by a hypercellular and dysplastic bone marrow, cytopenias resulting from impaired peripheral blood cell production, and an increased risk of leukemic transformation. Currently, azacitidine, decitabine, and lenalidomide are approved by the US Food and Drug Administration for the treatment of MDS. The DNA methyltransferase (DNMT) inhibitors such as azacitidine and decitabine have demonstrated the ability to alter the natural history of disease and thus prolong time to leukemic transformation. In addition, azacitidine has shown the capacity to extend survival compared with the previous gold standard of conventional care regimens. Recently, decitabine has been shown to be well tolerated with a toxicity profile expected for this class of agent. Recent studies also suggest that decitabine may result in additional improvements in response. As more is learned about the mechanism of hypomethylating agents, new roles are emerging for decitabine in combination therapy for MDS. The third agent, lenalidomide, is a thalidomide analogue with significant activity in a subset of patients with low-risk MDS, anemia and chromosome 5 alterations. Several other agents are being evaluated in MDS. This review summarizes the existing clinical experience on DNMT inhibitors and other drugs for the treatment of MDS.