Analysis of Proliferation Characters of Bone Marrow Mesenchymal Stem Cells Derived from Patients with Myelodysplastic Syndrome / 中国实验血液学杂志

OBJECTIVE@#To analyze the proliferation potential of bone marrow-derived mesenchymal stem cells (MSC) in patients with myelodysplastic syndrome (MDS).@*METHODS@#The MSC derived from the 24 patients with newly diagnosed MDS (MDS-MSC group) and MSC derived from 15 patients with nutritional anemia (control group) in the Affiliated Hospital of Hebei University were used as the research objects. The proliferation potential of MSC was analyzed by colony-forming unit assay, doubling time, cumulative passaging, cell number after 10 days of culture with equal amount of MSC and MTT experiment. The mechanism of abnormal proliferation was analyzed by cell cycle experiment, apoptosis experiment and p21 gene expression assay.@*RESULTS@#In the colony forming unit assay, the number of MDS-MSC colonies was 4.44±2.51, which was significantly lower than that of the control group (12.44±2.55)(P<0.01); the doubling time of MDS-MSC group was significantly longer than that of the control group (7.80±3.26 vs 3.63±0.85) (P<0.01); the number of MDS-MSC in 5×10@*CONCLUSION@#The proliferative capability of MDS-MSC is significantly reduced, which relates with the arrest of cell cycle in G

Research Advances on the Senescence Mechanism of Bone Marrow Mesenchymal Stem Cells Derived from Patients with Myelodysplastic Syndrome--Review / 中国实验血液学杂志

Emerging data have demonstrated that bone marrow mesenchymal stem cells (MSCs) play important roles in the progression of myelodysplastic syndrome (MDS). Experiments in vitro have showed that MSCs derived from MDS patients (MDS-MSC) exhibit the biological characteristics of cell senescence. Although the underlying mechanisms that regulate cell senescence need to be further elucidated, existing researches indicate that the mechanisms of MDS-MSC senescence have significant heterogeneity. Depth understanding of the underlying mechanisms involved in cell senescence of MDS-MSC are crucial to explore the potential therapeutic target of MDS. Therefore, this review summarizes research advances related with MSC senescence, such as MDS-MSC intrinsic changes in telomere shortening, DNA methylation status, oxidative stress and signal pathways regulating cell senescence in recent years.

Inhibitory Effect of Decitabine-inhibeting Methylation of SHP-1 Gene on Proliferation and Apoptosis of MDS Cell Line Skm-1 / 中国实验血液学杂志

OBJECTIVE@#To investigate the phenotype and molecular mechanism of DCA on MDS cell model, and to study the response of chemotherapeutic medicines to MDS cells through multiple dimensions, such as cell proliferation, invasion, migration and apoptosis, thus revealing the molecular mechanism of DCA treatment of MDS and its relationship with SHP-1 gene methylation.@*METHODS@#MTT assay was used to determine the survival rate of MDS cells after treated by different concentrations of DCA. The effect of DCA on the invasion and migration of MDS cells was detected by Transwell assay method. Apoplexin V-FITCPI was used to detect apoptosis, the MDS treatment on the mechanism of DCA was investigated by Western blot and Real-time PCR experiment.@*RESULTS@#According to the experiment, it was found that tumor proliferation could be inhibited when MDS skm-1 cells was treated by DCA, and the absorbance was lower and the inhibitory effect was more obvious in the 2.0, 5.0 μmol/L DCA group than in the 0.5 μmol/L DCA group and the negative control group. Compared with the control group, the number of MDS skm-1 cells crossing through the transwell upper chamber was significantly decreased after DCA application. After treated with 0.5, 2.0 and 5.0 μmol/L DCA, the apoptosis rate of MDS cells was 4.54%, 9.31% and 16.58% respectively, while the apoptosis rate of the control group was 3.20%, which shows the apoptosis rate increased significantly with the concentration of DCA. After treatment of MDS cell lines with different concentration of DCA, the methylation status of SHP-1 gene was decreased with the increase of drug concentration, the expression of SHP-1 was increased, the expression of STAT3 was decreased and the level of phosphorylation was decreased.@*CONCLUSION@#By analyzing the phenotypic response of DCA treatment on MDS cells, it was found that interfere with MDS can be performed by inhibiting proliferation, metastasis, and inducing apoptosis in a dose-dependent way. It revealed that the molecular mechanism by DCA treatment can improve the methylation of SHP-1 gene and inhibit the expression of p-STAT3.

Research advances of mesenchymal stem cells from bone marrow in myelodysplastic syndrome / 基础医学与临床

Myelodysplastic syndrome (MDS) is definded as a group of clonal hematological malignancies characterized by bone marrow (BM) ineffective.hematopoiesis and increases risk for progression to acute myeloid leukemia. The altered BM mesenchymal stem cells (MSCs) play a pivotal role in the evolution and propagation of MDS. Com-pared to normal MSCs, MSCs in MDS often exhibit altered Cytogenetic, epigenetic, differentiation and functional properties, moreover, high MSCs density is associated with poor prognostic factors, which translated into a signifi-cantly diminished ability to support normal hematopoiesis, facilitates survival of malignant hematopoietic cells, ulti-mately promote disease progression and transform to acute myeloid leukemia.Therefore, characterization of key steps in the pathogenesis of MDS will lead to new approaches to treat patients with this disease.

Mechanism and Its Countermeasure of Hypomethylating Agent Resistance in Patients with Myelodysplastic Syndrome--Review / 中国实验血液学杂志

Hypomethylating agents(HMA) currently are widely used in the treatment of myelodysplastic syndromes (MDS), provide a significant improvement in the treatment of MDS. However, resistance to HMA is an almost universal phenomenon. This review was focused on immune effects related to DNA methylation, and to explore the mechanism underlying HMA resistance involved in immune checkpoint pathways. However, the optimal role of checkpoint blockade therapy (CBT) and immune checkpoint pathways remain in HMA failure questionable. The better understanding of immune checkpoint pathways in resistance of HMA offers a compelling rationale to introduce CBT in patients as a novel treatment option. CBT is an established strategy in solid tumors with potential as an adjunctive therapy in hematologic malignancies, therefore, may alter the treatment landscape in MDS. The suitability and effectiveness of combining HMA with CBT need to be confirmed by the results of ongoing clinical trials, so as to find novel strategies to improve outcome after failure of HMA.

Senescent Mesenchymal Stem Cells Contribute to Progression of Myelodysplastic Syndromes-Review / 中国实验血液学杂志

Myelodysplastic syndromes (MDS) comprise a group of malignant hematopoietic stem cell (HSC) disorders characterized by ineffective hematopoiesis. The risk of transformation to acute myeloid leukemia (AML) is increasing. The initiating event in HSC of MDS leads to a growth advantage and subsequent clonal expansion, that is still poorly understood. Accumulating data indicate that the mesenchymal stem cells(MSCs) in MDS model display aberrant characteristics contributing to disease initiation and transformation into AML. MSC derived from MDS displayed the alteration in genetics, epigenetics and gene expression, which contribute to altered morphology, impaired proliferative and differentiation capacity and perturbed cytokine secretions, thus destroy in their ability to support normal hematopoiesis and contribute to malignant progression. A number of promising agents that target the interactions of the MDS clone with MSC are currently investigated in various phases of clinical trial, that might ultimately result in novel therapeutic strategies, targeting niche cells to attenuate leukemic progression. In this article, the current status of MDS treatment, the characteristics of MDS-MSC senescence and phenotypes, the changes of hematopoietic function sapported by senescent MDS-MSC, the significane of MDS-MSC in MDS prognosis and the MDS-MSC as potential target for treatment of MDS are summarized.

Lymphocyte Count before First Consolidation Therapy Is A Predictor of Relapse free Survival in Acute Myeloid Leukemia / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the effects of absolute lymphocyte count(ALC) before start of the first cycle of consolidation chemotherapy(CC) on the relapse free survival in the patients with acute myeloid leukemia(AML), so as to explore a simple and easy method for predicting AML relapse.</p><p><b>METHODS</b>The clinical data of 132 patients with newly diagnosed AML (all non-acute promyelotic leukemia) from 2011 to 2017 were analyzed retrospectively. The 132 AML patients were treated with standard induction chemotherapy (IC) and consolidation chemotherapy (CC). According to lymphocyte count of patients before start of the first cycle of CC, the AML patients were divided into 2 group: high lymphocyte count group (H-Lym≥1.2×10/L) and low lymphocyte count group (L-Lym<1.2×10/L). The differences in ralapse rate and relapse-free survival between 2 groups were analyzed.</p><p><b>RESULTS</b>Among 132 patients with AML, patients who could be valuated and were elicible for the study accounted for 65 (49.24%). The absolute leukocyte count, age, chromosome karyotypes before IC of patients did not show statistical difference between H-Lym group (40 cases) and L-Lym group (25 cases). Unvarvate analysis showed that the Low lymphocyte count and unfavorable chromosome karyotypes were poor prognostic factors for the relapse-free survival time, and there was significant difference between 2 groups (P<0.01). The relapse risk in patients of L-Lym group increased, the hazard ratio (HR)=3.01 (95% CI=1.55-4.98) (P<0.01). In multivariate analysis containing unfavorable prognostic karyotypes, this trend still existed (HR=2.52, 95% CI 1.28-9.98)(P<0.01).</p><p><b>CONCLUSION</b>The AML patients with high lymphocyte count before the first CC have more long relapse free survival time suggesting that the lymphocyte count before the first CC may be prognostic factor for relapse free survival of AML patients.</p>

The absolute value of lymphocyte counts and the response to decitabine treatment in patients with myelodysplastic syndrome / 解放军医学杂志

Objective To investigate the relations of absolute lymphocyte counts (ALC) to the therapeutic responses in patients with myelodysplastic syndrome (MDS) after the first course of decitabine (DAC) treatment.Methods Clinical data of 35 patients with MDS and MDS-derived secondary acute myeloid leukemia (AML) who were admitted in the Affiliated Hospital of Hebei University from Jan.2014 to Dec.2016 and treated with DAC were included in the present study.The patients were grouped into high lymphocyte group (H-Lym,ALC ≥ 1.2 × 109/L) and low lymphocyte group (L-Lym,ALC＜1.2 × 109/L) based on the ALC in days 28-35 after the first course of DAC treatment.The baseline data of both groups were compared with Pearson x2 analysis,while t test was used to analyze the changes of lymphocyte number before and after the first course of DAC treatment.Progressionfree survival (PFS) was estimated with Kaplan-Meier method,and the cumulative survival (CS) was compared between the two groups using log-rank test.Results Of the 35 patients,15 were in H-Lym group and 20 in L-Lym group.No significant difference existed in the baseline lymphocyte levels between the two groups (P＞0.05).The statistically significant differences (P＜0.05) existed only in the patients of the two groups who were with the proportion of bone marrow blasts ≥ 10％.The ALC in H-Lym group were slightly higher after the first course of DAC treatment than that at the time of diagnosis,but with no statistically significant (P＞0.05).However,the ALC in L-Lym group were significantly lower after the first course of DAC treatment than that at the time of diagnosis (P＜0.05).Patients had higher overall response rate (ORR) in H-Lym group than in L-Lym group (80％ vs.40％,P＜0.05).The median PFS was 10 months in H-Lym group and 7.6 months in L-Lym group (P＜0.05).Univariate analysis showed that the low ALC was a poor prognostic factor for the progression ofMDS (P＜0.05).Conclusion Patients with ALC ≥ 1.2 × 109/L after the first course of DAC treatment will have better ORR and longer PFS.

Predicting Therapeutic Response by Lymphocyte Level at 28th Day after DAC Treatment in Patients with MDS / 中国实验血液学杂志

OBJECTIVE@#To investigate a reliable clinical indication for predicting the therapeutic response of decitabine therapy in the patients with myelodysplastic syndromes (MDS).@*METHODS@#The clinical efficacy of decitabine for 55 cases of MDS was analyzed retrospectively. According to the lymphocyte level at d28 after the first time treatment with decitabine, the patients were divided into high lymphocyte level group (H-Lym≥1.2×10/L) and low lymphocyte level group (L-Lym<1.2×10/L), and the overall response rate (ORR) and the progression-free survival (PFS) time in 2 groups were compared.@*RESULTS@#As compared with L-Lym group, the ORR and PFS time in H-Lym group were significantly enhanced ［(76.0% vs 50.0%) (P<0.05) and median time (15.7 months vs 8.5 months)(P<0.05), respectively］;the ratio of platelet level ≥100×10/L in H-Lym group was very significantly higher than that in L-Lym group (72.0% vs 20.0%)(P<0.01). Multivariat analysis showed that the risk of disease progression in L-Lym group was 4.45-fold of H-Lym group (95% CI:1.58-12.59)(P<0.05).@*CONCLUSION@#The patients with lymphocyte level ≥1.2×10/L at day 28 after the first time treatment with decitabine show the higher ORR and longer PFS time, therefore. the lymphocyte level at day 28 after first time treatment with decitabine can be used as an early clinical indicator for predecting the response to decitabine treatment.

Research Advances of Molecular Genetic Abnormality in Myelodysplastic Syndrome--Review / 中国实验血液学杂志

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders characterized by ineffective hematopoiesis and increased risk of transformation to acute myelogenous leukemia (AML). The treatment of MDS is highly dependent on the reliability of the prognostic evaluation model. Current clinical prognostic scoring systems are comprised of morphology, pivotal clinical trials and cytogenetic findings. However, none of the available prognostic systems incorporates disease-related molecular abnormalities, such as somatic mutations. Cumulative evidence suggests that genomic data can also be used clinically to assist the diagnosis, prognosis, prediction of response to specific therapies, and the development of novel and accurate targeted therapies. Therefore, it is not possible to predict the response of patients to molecular targeted drugs, such as demethylation drugs. With the recent advance in whole- genome sequencing technologies, cumulative evidence suggests that genomic data can also be associated with the genesis, prognosis, prediction of response to specific therapies, and the development of novel accuvate targeted therapies, the issue of having some mechanism to dissect this heterogeneity and precision treatment is coming to the fore. However, there are still several hindrances to its clinical application. If these problems can be solved, molecular genetics will further provide a theoretical basis for the application of precision medicine in MDS.