miR-103-3p regulates the differentiation of bone marrow mesenchymal stem cells in myelodysplastic syndrome

The pathogenesis of myelodysplastic syndrome(MDS)may be related to the abnormal expression of microRNAs(miRNAs),which could influence the differentiation capacity of mesenchymal stem cells(MSCs)towards adipogenic and osteogenic lineages.In this study,exosomes from bone marrow plasma were successfully extracted and identified.Assessment of miR-103-3p expression in exosomes isolated from BM in 34 MDS patients and 10 controls revealed its 0.52-fold downregulation in patients with MDS compared with controls(NOR)and was downregulated 0.55-fold in MDS-MSCs compared with NOR-MSCs.Transfection of MDS-MSCs with the miR-103-3p mimic improved osteogenic differentiation and decreased adipogenic differentiation in vitro,while inhibition of miR-103-3p showed the opposite results in NOR-MSCs.Thus,the expression of miR-103-3p decreases in MDS BM plasma and MDS-MSCs,significantly impacting MDS-MSCs differentiation.The miR-103-3p mimics may boost MDS-MSCs osteogenic differentiation while weakening lipid differentiation,thereby providing possible target for the treatment of MDS pathogenesis.

Severe inflammatory disorder in trisomy 8 without myelodysplastic syndrome and response to methylprednisolone:A case report

BACKGROUND Patients with trisomy 8 consistently present with myeloid neoplasms and/or auto-inflammatory syndrome.A possible link between myelodysplastic syndromes(MDS)with trisomy 8(+8-MDS)and inflammatory disorders is well recognized,several cases having been reported.However,inflammatory disorders in patients without MDS have been largely overlooked.Generally,Behçet's disease is the most common type in+8-MDS.However,inflammatory disorders with pulmonary involvement are less frequent,and no effective treatment has been established.CASE SUMMARY A 27-year-old man with recurrent fever,fatigue for>2 mo,and unconsciousness for 1 day was admitted to our emergency department with a provisional diagnosis of severe pneumonia.Vancomycin and imipenem were administered and sputum collected for metagenomic next-generation sequencing.Epstein–Barr virus and Mycobacterium kansasii were detected.Additionally,chromosomal analysis showed duplications on chromosome 8.Two days later,repeat metagenomic next-generation sequencing was performed with blood culture.Cordyceps portugal,M.kansasii,and Candida portugal were detected,and duplications on chromosome 8 confirmed.Suspecting hematological disease,we aspirated a bone marrow sample from the iliac spine,examination of which showed evidence of infection.We added fluconazole as further antibiotic therapy.Seven days later,the patient’s condition had not improved,prompting addition of methylprednisolone as an anti-inflammatory agent.Fortunately,this treatment was effective and the patient eventually recovered.CONCLUSION Severe inflammatory disorders with pulmonary involvement can occur in patients with trisomy 8.Methylprednisolone may be an effective treatment.

Flared inflammatory episode transforms advanced myelodysplastic syndrome into aplastic pancytopenia:A case report and literature review

BACKGROUND Myelodysplastic syndrome(MDS)is a hematological neoplasm,and an increase in myeloblasts is representative of leukemic hematopoiesis in advanced MDS.Lowrisk MDS usually exhibits deranged autoimmunity resembling that of aplastic anemia(AA),whereas advanced MDS is characterized by a phenotype of immune exhaustion.MDS can be normo/hyperplastic or hypoplastic.Generally,bone marrow cellularity and myeloblasts increase with disease progression.Transformation from advanced MDS to AA-like syndrome with leukemic cell regression has not previously been reported.CASE SUMMARY A middle-aged Chinese woman had a 4-year history of leukocytopenia.Six months prior to admission,the patient developed gradually worsening fatigue and performance status.The leukocytopenia further progressed.She was diagnosed with MDS with excess blasts-2 based on increased bone marrow cellularity and an increased percentage of myeloblasts on marrow and blood smears,an increased percentage of cluster of differentiation(CD)34+CD33+progenitors in immunotyping analysis,a normal karyotype in cytogenetic analysis,and the identification of somatic mutations in CBL,KMT2D and NF1 in molecular analysis.Initially,neutropenia was the predominant hematological abnormality,with mild anemia and thrombocytosis,and the degree of fatigue was far more severe than the degree of anemia.In the following months,the patient experienced several febrile episodes.Intravenous antibiotic treatments were able to control the febrile episodes,but the elevated inflammatory indices persisted.The hematological parameters dramatically fluctuated with the waxing and waning of the inflammatory episodes.With recurrent flares of the inflammatory condition,agranulocytosis and severe anemia developed,with mild thrombocytopenia.During the patient’s hospitalization,computed tomography(CT)scans revealed the presence of extensive inflammatory lesions involving the lungs,mediastinum,pleura,gastrointestinal tract,peritoneum and urinary tract,with imaging features suggestive of the reactivation of disseminated tuberculosis.Reevaluation of the bone marrow smears revealed that the cellularity became hypoplastic,and the leukemic cells regressed,suggesting that both normal and leukemic hematopoiesis had been heavily suppressed.Immunological analysis of the bone marrow samples revealed a decreased percentage of CD34+cells and an immunological signature resembling that of severe AA(SAA),confirming the regression of the leukemic cells by autoimmune-mediated attacks.The patient demonstrated resistance to multiple drugs,including antituberculotics,recombinant human granulocyte colony-stimulating factor,broad-spectrum antibiotics,voriconazole,ganciclovir,immune suppressants,eltrombopag and intravenous immunoglobulin,which further worsened the hematological injury and patient’s performance status.The patient eventually died of overwhelming infection and multidrug resistance.CONCLUSION Advanced MDS can transform to aplastic cytopenia with leukemic cell regression and an immunological signature of SAA during inflammatory flare-ups.

Tuberculosis-induced aplastic crisis and atypical lymphocyte expansion in advanced myelodysplastic syndrome:A case report and review of literature

BACKGROUND Myelodysplastic syndrome(MDS)is caused by malignant proliferation and ineffective hematopoiesis.Oncogenic somatic mutations and increased apoptosis,necroptosis and pyroptosis lead to the accumulation of earlier hematopoietic progenitors and impaired productivity of mature blood cells.An increased percentage of myeloblasts and the presence of unfavorable somatic mutations are signs of leukemic hematopoiesis and indicators of entrance into an advanced stage.Bone marrow cellularity and myeloblasts usually increase with disease progression.However,aplastic crisis occasionally occurs in advanced MDS.CASE SUMMARY A 72-year-old male patient was definitively diagnosed with MDS with excess blasts-1(MDS-EB-1)based on an increase in the percentages of myeloblasts and cluster of differentiation(CD)34+hematopoietic progenitors and the identification of myeloid neoplasm-associated somatic mutations in bone marrow samples.The patient was treated with hypomethylation therapy and was able to maintain a steady disease state for 2 years.In the treatment process,the advanced MDS patient experienced an episode of progressive pancytopenia and bone marrow aplasia.During the aplastic crisis,the bone marrow was infiltrated with sparsely distributed atypical lymphocytes.Surprisingly,the leukemic cells disappeared.Immunological analysis revealed that the atypical lymphocytes expressed a high frequency of CD3,CD5,CD8,CD16,CD56 and CD57,suggesting the activation of autoimmune cytotoxic T-lymphocytes and natural killer(NK)/NKT cells that suppressed both normal and leukemic hematopoiesis.Elevated serum levels of inflammatory cytokines,including interleukin(IL)-6,interferon-gamma(IFN-γ)and tumor necrosis factor-alpha(TNF-α),confirmed the deranged type I immune responses.This morphological and immunological signature led to the diagnosis of severe aplastic anemia secondary to large granule lymphocyte leukemia.Disseminated tuberculosis was suspected upon radiological examinations in the search for an inflammatory niche.Antituberculosis treatment led to reversion of the aplastic crisis,disappearance of the atypical lymphocytes,increased marrow cellularity and 2 mo of hematological remission,providing strong evidence that disseminated tuberculosis was responsible for the development of the aplastic crisis,the regression of leukemic cells and the activation of CD56+atypical lymphocytes.Reinstitution of hypomethylation therapy in the following 19 mo allowed the patient to maintain a steady disease state.However,the patient transformed the disease phenotype into acute myeloid leukemia and eventually died of disease progression and an overwhelming infectious episode.CONCLUSION Disseminated tuberculosis can induce CD56+lymphocyte infiltration in the bone marrow and in turn suppress both normal and leukemic hematopoiesis,resulting in the development of aplastic crisis and leukemic cell regression.

Clinical management of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes

The myelodysplastic/myeloproliferative neoplasms(MDS/MPNs) are a unique group of hematologic malignancies characterized by concomitant myelodysplastic and myeloproliferative features. According to the 2008 WHO classification, the category includes atypical chronic myeloid leukemia(a CML), chronic myelomonocytic leukemia(CMML), juvenile myelomonocytic leukemia(JMML), MDS/MPN-unclassifiable(MDS/MPN-U), and the provisional entity refractory anemia with ring sideroblasts and thrombocytosis(RARS-T). Although diagnosis currently remains based on clinicopathologic features, the incorporation of nextgeneration platforms has allowed for the recent molecular characterization of these diseases which has revealed unique and complex mutational profiles that support their distinct biology and is anticipated to soon play an integral role in diagnosis,prognostication, and treatment. Future goals of research should include the development of disease-modifying therapies, and further genetic understanding of the category will likely form the foundation of these efforts.

Platelet Doubling After First Decitabine Cycle Predicts Response and Survival of Myelodysplastic Syndrome Patients

Objective:Although the effect of decitabine on myelodysplastic syndrome(MDS)has been demonstrated,merely a proportion of patients respond to therapy,and no well-recognized predictors have been identified.This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice,and determine the predictive factors of response and overall survival(OS)in MDS patients.

Concurrent ankylosing spondylitis and myelodysplastic syndrome:A case report

BACKGROUND Ankylosing spondylitis(AS)is an autoimmune disease characterized by sacroiliitis and spondylitis,with a few hematological abnormalities.Myelodysplastic syndromes(MDS)are a heterogeneous group of hematopoietic stem cell disorders with frequent autoimmune phenomena.The relationship between AS and MDS remains unknown.CASE SUMMARY We describe a rare case of concurrent AS and MDS.An 18-year-old man with low back pain and anemia was diagnosed with AS;however,the cause of anemia could not be determined by the first bone marrow examination.He recovered from anemia and the symptoms of AS resolved after treatment with etanercept,glucocorticoid,and blood transfusion,but he developed pancytopenia with an increased myeloblast count(from 2.5%to 9%).Chromosome analysis revealed del(7q)and trisomy 8.Refractory anemia with excess of blasts-1(RAEB-1)/MDS was confirmed by repeating the bone marrow examination.He became blood transfusion-dependent and received decitabine-based chemotherapy but eventually died.CONCLUSION We suspect that AS may be an early autoimmune phenomenon related to MDS.However,a condition of coexistence cannot be excluded.

Novel spontaneous myelodysplastic syndrome mouse model

Background:Myelodysplastic syndrome(MDS)is a group of disorders involving he-mopoietic dysfunction leading to leukemia.Although recently progress has been made in identifying underlying genetic mutations,many questions still remain.Animal models of MDS have been produced by introduction of specific mutations.However,there is no spontaneous mouse model of MDS,and an animal model to simulate natu-ral MDS pathogenesis is urgently needed.Methods:In characterizing the genetically diverse mouse strains of the Collaborative Cross(CC)we observed that one,designated JUN,had abnormal hematological traits.This strain was thus further analyzed for phenotypic and pathological iden-tification,comparing the changes in each cell population in peripheral blood and in bone marrow.Results:In a specific-pathogen free environment,mice of the JUN strain are rela-tively thin,with healthy appearance.However,in a conventional environment,they become lethargic,develop wrinkled yellow hair,have loose and light stools,and are prone to infections.We found that the mice were cytopenic,which was due to abnor-mal differentiation of multipotent bone marrow progenitor cells.These are common characteristics of MDS.Conclusions:A mouse strain,JUN,was found displaying spontaneous myelodysplas-tic syndrome.This strain has the advantage over existing models in that it develops MDS spontaneously and is more similar to human MDS than genetically modified mouse models.JUN mice will be an important tool for pathogenesis research of MDS and for evaluation of new drugs and treatments.

EARLY DIAGNOSIS OF MYELODYSPLASTIC SYNDROMES USING CLONAL ANALYSES

Objective: To study the value of clonal analysis to the early diagnosis of myelodysplastic syndrome (MDS). Methods: Four types of clonal analyses were performed on the bone marrow samples from 50 patients suspected of MDS: (1) Conventional Cytogenetics (CC) for clonal chromosomal abnormalities; (2) BrdU-Sister Chromatid Differentiation (BrdU-SCD) for cell cycle kinetics; (3) Fluorescence in Situ Hybridization (FISH) for trisomy 8; (4) Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) for N-ras mutation. Results: The diagnosis of forty-three patients was compatible with the FAB criteria for MDS. The other seven cases didn’t meet the FAB criteria, with only one lineage of dyspoiesis or with no obvious dysplastic changes. Among these seven cases, two were morphologically diagnosed with suspicious refractory anemia, one with sideroblastic anemia, one with leukemoid reaction, one with hypercellular anemia and two with chronic aplastic anemia. Clonal analyses of the 7 patients showed that six cases had clonal karyotype abnormalities, four had prolonged cell cycle patterns, four had trisomy 8 of different proportions and one had mutation of the exon 1 of N-RAS. Thus, they were revaluated as MDS patients. Conclusion: The untypical MDS patients with one lineage dyspoiesis or without obvious dysplastic changes can be diagnosed early by combining multiple clonal analysis techniques such as CC, SCD, FISH and PCR-SSCR.

Successful treatment in one myelodysplastic syndrome patient with primary thrombocytopenia and secondary deep vein thrombosis:A case report

BACKGROUND The contradictory process of coagulation and anticoagulation maintains normal physiological function,and platelets(PLTs)play a key role in hemostasis and bleeding.When severe thrombocytopenia and deep vein thrombosis(DVT)occur simultaneously,the physician will be confronted with a great challenge,especially when interventional thrombectomy fails.CASE SUMMARY We describe a 52-year-old woman who suffered from myelodysplastic syndrome with severe thrombocytopenia and protein S deficiency with right lower extremity DVT.In this patient,the treatment of DVT was associated with numerous contradictions due to severe thrombocytopenia,especially when interventional thrombectomy was not successful.Fortunately,fondaparinux sodium effectively alleviated the thrombus status of the patient and gradually decreased the D-dimer level.In addition,no increase in bleeding was noted.The application of eltrombopag stimulated the maturation and differentiation of megakaryocytes and increased the peripheral blood PLT count.The clinical symptoms of DVT in the right lower extremities in this patient significantly improved.The patient resumed daily life activities,and the treatment effects were independent of PLT transfusion.CONCLUSION This is a contradictory and complex case,and fondaparinux sodium and eltrombopag may represent a good choice for the treatment of DVT in patients with severe thrombocytopenia.

Del(5q) and inv(3) in myelodysplastic syndrome: A rare case report

BACKGROUND Del(5q)is the most common molecular event in myelodysplastic syndrome(MDS),accounting for 10%-15%of cases.Inv(3)is an adverse cytogenetic abnormality observed in less than 1%of MDS patients.Few studies have reported the coexistence of del(5q)and inv(3)in MDS.Therefore,the pathological mechanism,treatment strategy and prognosis of this subtype need to be elucidated.CASE SUMMARY A 66-year-old woman was admitted to the hospital due to chest tightness and shortness of breath.Combining clinical assessments with laboratory examinations,the patient was diagnosed with MDS containing both del(5q)and inv(3).Considering the deletion of chromosome 5q,we first treated the patient with lenalidomide.When drug resistance arose,we tried azacitidine,and the patient had a short remission.Finally,the patient refused treatment with haematopoietic stem cell transplantation and died of severe infection four months later.CONCLUSION MDS patients with del(5)and inv(3)have a poor prognosis.Azacitidine may achieve short-term remission for such patients.

Remarkably different results between two studies from North America on genomic mutations and sensitivity to DNA demethylating agents for myelodysplastic syndromes

Sekeres et al. （1） conducted a multicenter randomized, controlled trial to compare whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates to azacitidine in the treatment of myelodysplastic syndromes （MDS）. In that trial, 224 patients with higher-risk MDS and 53 with chronic myelomonocytic leukemia （CMML） were enrolled and randomly assigned to the ＂azacitidine＂ group, ＂azacitidine plus lenalidomide＂ group or ＂azacitidine plus vorinostat＂ group. The researchers found that patients with MDS treated with azacitidine-based combinations had similar response rate to azacitidine monotherapy. Using genomic mutation analysis, they found that the overall response rate to azacitidine-based treatment was higher for patients with mutations in DNMT3A and lower for those with mutations in SRSF2. Whereas in another study, Welch et al. enrolled 26 patients with MDS and 90 with acute myeloid leukemia （AML） who were treated with decitabine, and they found that patients with TP53 mutations had a higher response rate, but not those with DNMT3A mutations （2）. We propose that this big discrepancy in the conclusions between the two studies might have been caused by the presence of many co-interacting factors, e.g. study aims, DNA demethylating agents, treatment protocols, and patient sources.

Myelodysplastic Syndrome Secondary to Multiple Myeloma: A Case Report and Literature Review

Background: With the prolongation of survival in recent years, the accumulation of toxic and side effects of therapeutic drugs and the concomitant drug-related adverse reactions were reported in recent years. However, myelodysplastic syndrome secondary to multiple myeloma is rare. Objective: To improve the understanding of myelodysplastic syndrome secondary to multiple myeloma. Methods: The clinical data of a patient with myelodysplastic syndrome secondary to multiple myeloma after treatment were analyzed, and the related literature was reviewed. Results: A 54-year-old male patient was diagnosed as multiple myeloma in February 2014. After three courses of first-line induction chemotherapy, he achieved complete remission and received two courses of consolidation treatment. After that, he continued to take thalidomide orally. The disease recurred 13 months after complete remission (CR) with 6q+ karyotype change in 37 months. 21q- karyotype change was found in 39 months. The patient was finally diagnosed as treatment-related secondary myelodysplastic syndrome. Due to the poor effect of chemotherapy, the disease continued to deteriorate. Conclusion: In the course of multiple drug treatment, clinicians should pay attention to the changes of molecular genetics and the treatment-related secondary tumor.

Summary of animal models of myelodysplastic syndrome

Myelodysplastic syndrome(MDS)is a malignant tumor of the hematological system characterized by long-term,progressive refractory hemocytopenia.In addition,the risk of leukemia is high,and once it develops,the course of acute leukemia is short with poor curative effect.Animal models are powerful tools for studying human diseases and are highly effective preclinical platforms.Animal models of MDS can accurately show genetic aberrations and hematopoietic clone phenotypes with similar cellular features(such as impaired differentiation and increased apoptosis),and symptoms can be used to assess existing treatments.Animal models are also helpful for understanding the pathogenesis of MDS and its relationship with acute leukemia,which helps with the identification of candidate genes related to the MDS phenotype.This review summarizes the current status of animal models used to research myelodysplastic syndrome(MDS).

A case of myelodysplastic syndromes with initial symptom of erythra

Myelodysplastic syndrome(MDS)is a malignant clonal disease of human hematopoietic stem cells.In this paper,a case of MDS with fever and rash as the first symptom was reported in our hospital,and the related literature was reviewed and summarized to provide ideas for the diagnosis of MDS.Case summary:The patient,male,62 years old,with systemic rash and fever as the initial symptoms,early multiple bone marrow examination showed no typical abnormalities.With the progress of the disease,bone marrow cytology,flow cytometry,molecular karyotype,chromosomal karyotype,skin biopsy and pathological diagnosis were performed,and the diagnosis was MDS.

Partial Trisomy 1q21-qter and Partial Monosomy 7q21-qter Due to a Derivative Chromosome 7 in Myelodysplastic Syndrome Associated with Squamous Cell Carcinoma: Case Report

Background: Myelodysplastic syndromes (MDS) are subtypes of hematological disorders which are known to have partial bone marrow dysplasia, peripheral cytopenia, and later on an increased risk to develop acute myeloid leukemia. Chromosomal aberrations are detected in ~50% of cases of de novo MDS cases and the most common chromosomal abnormalities of this entity include complete or partial monosomy of chromosomes 5 and 7, partial deletion of 20q and 12p, trisomy 8, and 11q23 aberrations. A few primary and/or secondary MDS cases combined with other cancer have been reported. Case Presentation: We report here an adult MDS associated with squamous cell carcinoma (SCC). G-banding and array-proven multicolor banding (aMCB) revealed an unbalanced translocation der(7)t(1;7)(q21;q21), which led to 1q partial trisomy and 7q partial monosomy. Immunophenotype of this case was consistent with refractory anemia with excess of blasts (RAEB-2) according to World Health Organization (WHO) classification. Conclusions: As far as we know, this is the first adult MDS case associated with SCC and an unbalanced translocation t(1;7). Our patient received first cycle of azacitidine treatment and he showed bilateral pleural effusion as a secondary event. This toxicity is not limited to the first cycle as in previous MDS cases;our case is the first one to shown this toxicity as a secondary event of azacitidine treatment. As less than 10 cytogenetcially comparable cases without SCC were reported before in male MDS, we carefully conclude that this cytogenetic aberration may be a hint on a new gender associated MDS subgroup.

Exploration of the molecular mechanism of Indigo Naturalis in the treatment of myelodysplastic syndromes through integrated pharmacological study

Background:Oral administration of indigo naturalis(IN)is used as a complementary and alternative medicine(CAM)regimen for the treatment of myelodysplastic syndromes(MDS).However,its mechanism of action has not been fully elucidated and needs to be further explored.Methods:By searching the traditional Chinese medicine system and analyzing platforms(TCMSP),bioinformatics analysis tool for the molecular mechanism of traditional Chinese medicine(BATMAN-TCM),and Swiss Target Prediction network database,the main active components and potential targets of IN were obtained.Based on this,a component-target network was established by Cytoscape 3.6.1 software.Differentially expressed genes(DGEs)in MDS were obtained from three GEO(Gene Expression Omnibus)gene chips.Then,the protein-protein interaction(PPI)network of DGEs was constructed and analyzed by STRING database and Cytoscape 3.6.1 software.In addition,Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)biological enrichment analysis were carried out using REVIGO and KEGG Orthology Based Annotation System(KOBAS)on DGEs,respectively.Identification of IN-MDS compound targets was performed by matching potential targets of active components with disease-related targets.The results of KEGG pathway enrichment analysis were combined with compound targets to screen key targets.In the end,molecular docking was performed by SYBYL-X2.1 to verify the key targets.Results:Nine active components of IN and 439 potential targets of IN were identified by analyzing TCMSP,BATMAN-TCM,and Swiss Target Prediction network databases.Three MDS disease-related gene microarray chips were obtained from the GEO databases:GSE4619,GSE19429,and GSE58831.Through this analysis,87 DEGs were finally obtained using the Venn diagram.A PPI network of DEGs was then constructed,in which 18 genes were upregulated and 69 genes were downregulated.After the GO enrichment results were de-redundant,the representative GO terms were obtained by using REVIGO semantic similarity measuremen.The KEGG biological pathway analysis using the KOBAS indicated that the Hippo signaling pathway is important in MDS.The Hippo signaling pathway involves four genes:AREG,LEF1,SMAD7,and TCF4.By matching and mapping DEGs with potential targets,six IN-MDS compound targets were obtained:PDE4B,PLAUR,ELANE,NR3C1,AREG,and LEF1.We found that AREG and LEF1 are consistent with the genes involved in the Hippo signaling pathway.Through molecular docking simulation,we found that the indican binds best to AREG and LEF1.Conclusion:Based on the integrated pharmacology model,the material basis of the efficacy and biological molecular mechanism of IN in the treatment of MDS was systematically studied,which provided a novel indication of the CAM regimen for the improvement of MDS management.

Evaluation of the Therapeutic Significance of Arsenite and Thalidomide in Patients with Myelodysplastic Syndrome

Objective:To analyze the therapeutic significance of arsenite and thalidomide in patients with myelodysplastic syndrome.Methods:From August 2021 to August 2022,80 patients with myelodysplastic syndrome were selected and randomly divided into two groups.In the control group,the drug used was thalidomide tablets,whereas in the observation group,the drug used was arsenite and thalidomide.The treatment effect was observed and evaluated.Results:Before treatment,there was no statistical significance in the blood and serological indices between the two groups.After treatment,the observation group showed better blood and serological indices than the control group(P<0.05).The clinical efficacy of the observation group was 77.5%,while that of the control group was 50.0%.The observation group had significantly better treatment effect(P<0.05).The incidence of adverse effects in the observation group and the control group was 5.0%and 20.0%,respectively.The observation group had significantly fewer adverse effects(P<0.05).Conclusion:In the treatment of patients with myelodysplastic syndrome,the use of arsenite on the basis of thalidomide can effectively improve the treatment effect and optimize the levels of various blood and serological indices,with fewer adverse effects and a relatively high safety profile.

Efficacy of Yisui granule(益髓颗粒)on myelodysplastic syndromes in SKM-1 mouse xenograft model through suppressing Wnt/β-catenin signaling pathway

OBJECTIVE:To unmask the underlying mechanisms of Yisui granule(益髓颗粒,YSG)for the treatment of Myelodysplastic syndromes(MDS).METHODS:Our study used an SKM-1 mouse xenograft model of MDS to explore the anti-tumor potential of YSG and its safety,assess its effect on overall survival(OS),and evaluate whether its mechanism is associated with the demethylation of the secreted frizzled related protein 5(s FRP5)gene and suppressing Wnt/β-catenin pathway.Bisulfite amplicon sequencing was applied to detect the level of methylation of the s FRP5 gene;western blotting,immunofluorescence staining,and real-time Polymerase Chain Reaction were performed to detect DNA methyltransferase 1(DNMT1),s FRP5,and other Wnt/β-catenin pathway-related m RNA and protein expression.RESULTS:The results showed that high-dosage YSG exerted an anti-tumor effect similar to that of decitabine,improved OS,and reduced long-term adverse effects in the long term.Mechanically,YSG reduced the expression of DNMT1 methyltransferase,decreased the methylation,and increased the expression of the Wnt/β-catenin pathway antagonist-s FRP5.Furthermore,components of the Wnt/β-catenin pathway,including Wnt3a,β-catenin,c-Myc,and cyclin D1,were down-regulated in response to YSG,suggesting that YSG could treat MDS by demethylating the s FRP5 gene and suppressing the Wnt/β-catenin pathway.CONCLUSIONS:Our findings demonstrated that YSG could be used alone or in combination with decitabine to improve outcomes in the MDS animal model,providing an alternative solution for treating MDS.

De novo myelodysplastic syndrome in a Rothmund-Thomson Syndrome patient with novel pathogenic RECQL4 variants

Rothmund-Thomson syndrome(RTS)is a rare autosomal-recessive disorder with clinical features consisting of rash,poikiloderma,sparse hair,short stature,juvenile cataracts,skeletal abnormalities,and cancer predisposition.Genetic studies involving detection of pathogenic RECQL4 variants provide the diagnostic certitude.Osteosarcoma was found in two-thirds RECQL4-mutated RTS patients,while hematological malignancies were rarely reported.The variant diversity of RECQL4 gene has not been fully identified and mutations associated with hematologic malignancies are not well described.In this study,we presented a pedigree of RTS from a Chinese family,among which the proband was diagnosed with de novo myelodysplastic syndrome(MDS).Comprehensive medical examination and chromosome karyotyping were performed on the proband.Whole exome sequencing(WES)was performed on the proband,his sister and his mother.The familial cosegregation of sequence variants derived from WES was conducted by polymerase chain reaction–based Sanger sequencing.Structures of candidate RECQL4 mutants were done by in silico analysis to assess pathogenicity.Three novel RECQL4 germline variants,including c.T274C,c.G3014A,and c.G801C,were identified by WES and validated by Sanger sequencing.Prediction of conformation indicated that the structural stability of human RECQL4 protein was largely affected with these variants.The co-occurring U2AF1 p.S34F and TP53 p.Y220C mutations might contribute to the development of MDS.Our study expands the mutational spectrum of RECQL4 and provides underlying molecular mechanism for the development of MDS in RTS patients.