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.

Characteristics of Clostridium difficile infection in patients hospitalized with myelodysplastic syndrome or acute myelogenous leukemia

AIM To evaluate factors associated with Clostridium difficile infection (CDI) and outcomes of CDI in the myelodysplastic syndrome(MDS) and acute myeloid leukemia (AML) population.METHODS After IRB approval,all MDS/AML patients hospitalized at the University of Maryland Greenebaum Comprehensive Cancer Center between August 2011 and December 2013 were identified.Medical charts were reviewed for demographics,clinical information,development of CDI,complications of CDI,and mortality.Patients with CDI,defined as having a positive stool PCR done for clinical suspicion of CDI,were compared to those without CDI in order to identify predictors of disease.A t-test was used for comparison of continuous variables and chisquare or Fisher's exact tests were used for categorical variables,as appropriate.RESULTS Two hundred and twenty-three patients (60.1% male,mean age 61.3 years,13% MDS,87% AML) had 594 unique hospitalizations during the study period.Thirtyfour patients (15.2%) were diagnosed with CDI.Factors significantly associated with CDI included lower albumin at time of hospitalization (P < 0.0001),prior diagnosis of CDI (P < 0.0001),receipt of cytarabine-based chemotherapy (P = 0.015),total days of neutropenia (P = 0.014),and total days of hospitalization (P = 0.005).Gender (P = 0.10),age (P = 0.77),proton-pump inhibitor use (P = 0.73),receipt of antibiotics (P = 0.66),and receipt of DNA hypomethylating agent-based chemotherapy (P = 0.92) were not significantly associated with CDI.CONCLUSION CDI is common in the MDS/AML population.Factors significantly associated with CDI in this population include low albumin,prior CDI,use of cytarabine-based chemotherapy,and prolonged neutropenia.In this study,we have identified a subset of patients in which prophylaxis studies could be targeted.

Identification of SNP-containing regulatory motifs in the myelodysplastic syndromes model using SNP arrays and gene expression arrays

Myelodysplastic syndromes have increased in frequency and incidence in the American population, but patient prognosis has not significantly improved over the last decade. Such improvements could be realized if biomarkers for accurate diagnosis and prognostic stratification were successfully identified. In this study, we propose a method that associates two state-of-the-art array technologies-single nucleotide polymorphism (SNP) array and gene expression array-with gene motifs considered transcription factor -binding sites (TFBS). We are particularly interested in SNP-containing motifs introduced by genetic variation and mutation as TFBS. The potential regulation of SNP-containing motifs affects only when certain mutations occur. These motifs can be identified from a group of co-expressed genes with copy number variation. Then, we used a sliding window to identify motif candidates near SNPs on gene sequences. The candidates were filtered by coarse thresholding and fine statistical testing. Using the regression-based LARS-EN algorithm and a level-wise sequence combination procedure, we identified 28 SNP-containing motifs as candidate TFBS. We confirmed 21 of the 28 motifs with ChIP-chip fragments in the TRANSFAC database. Another six motifs were validated by TRANSFAC via searching binding fragments on coregulated genes. The identified motifs and their location genes can be considered potential biomarkers for myelodysplastic syndromes. Thus, our proposed method, a novel strategy for associating two data categories, is capable of integrating information from different sources to identify reliable candidate regulatory SNP-containing motifs introduced by genetic variation and mutation.

Early Detection of Myelodysplastic Syndrome/Leukemia-associated Mutations Using NGS Is Critical in Treating Aplastic Anemia

Distinguishing between aplastic anemia(AA)and hypoblastic myelodysplastic syndrome(hMDS)with a low percentage of bone marrow(BM)blasts(<5%)can be difficult due to the overlap in clonality and a spectrum of genetic alternations between the two subtypes of diseases.However,due to recent advances in DNA sequencing technology,both spectnim and frequency of mutations can be accurately determined and monitored by next-generation sequencing(NGS)at initial diagnosis and during immunosuppressive therapy(1ST)in patients with AA or hMDS.This improvement in acquiring a patient's genetic status and clonal evolution can provide more proper,precise,and on-time information to guide disease management,which is especially helpful in the absence of traditional morphologic/cytogenetic evidence.

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.

TET2 Expression in Bone Marrow Mononuclear Cells of Patients with Myelodysplastic Syndromes and Its Clinical Significances

Objective To investigate the expression of TET2 mRNA and protein in the bone marrow mononuclear cells(BMMNC) of patients with myelodysplastic syndrome(MDS) and its clinical significance. Methods The expression of TET2 mRNA and protein in bone marrow mononuclear cells(BMMNC) of 32 patients with MDS and 20 healthy donors was examined by qPCR and Western blot. Results The expression of TET2 mRNA in BMMNC was down-regulated in MDS patients compared with the donor group [(0.41±0.28)%vs.(1.07±0.56)%](P<0.001).Compared with lower expression group(TET2<0.4)[(6.53±6.17)%],patients with higher expression of TET2(≥0.4) presented significantly lower proportion of bone marrow blasts[(1.21±1.56)%](P<0.05).The expression of TET2 mRNA in BMMNC of MDS patients was inversely correlated with malignant clone burden(r=-0.398,P<0.05) and IPSS(r=-0.412, P<0.05).The expression of TET2 protein was down-regulated in MDS patients compared with that in the donor group. Conclusions The mRNA and protein expression of TET2 in BMMNC of MDS patients is decreased,which might be useful as an important parameter for the evaluation of MDS clone burden.

Large-vessel thrombosis in intestinal Behet's disease complicated with myelodysplastic syndrome and trisomy 8

Behet's disease is characterized by recurrent oral ulcers, genital ulcers, uveitis and skin lesions. Myelodysplastic syndrome (MDS) is characterized by problems due to ineffective hematopoiesis. Several studies have identified a relationship between MDS and Behet's disease, especially intestinal Behet's disease. Trisomy 8 seems to play an important role in these disorders as well. The present case was a 24-year-old woman who had a huge tonsil ulcer with initial symptoms of odynophagia and intermittent fever. We also noted folliculitis on her upper back. Five days later, she began to experience diarrhea and abdominal pain. Abdominal computed tomography and subsequent surgery revealed ileum perforation and enterocolitis with multiple ulcers. Later, she was admitted again for a vulvar suppurative ulcer and suspicious Bartholin's cyst infection. The patient's clinical presentations met the criteria for Behet's disease. Six months after the bowel perforation event, we noted the development of pancytopenia in a routine laboratory examination. All the examinations led to the diagnosis of MDS with trisomy 8. The most unusual finding was that multiple large vessel thrombi developed during follow-up. Previous studies have suggested that trisomy 8 in MDS leads to concurrent intestinal Behet's disease. Moreover, the inflammatory and immune genes related to thrombus formation are overexpressed in cases of MDS with trisomy 8. Trisomy 8 must play a role in thrombosis. Further studies are needed to help clarify the pathophysiology and pathogenesis of these disorders.

More Benefits of Oral Administration of Arsenic-containing Qinghuang Powder Compared with Decitabine for High/Very-high Risk Myelodysplastic Syndrome

OBJECTIVE: To evaluated the benefits of oral administration of arsenic-containing Qinghuang Powder(QHP)compared with decitabine for patients with high/very-high(H/VH) risk myelodysplastic syndrome(MDS) according to the Revised International Prognostic Score System. METHODS: The OS(mOS) rate, annual OS rate and progression to acute myeloid leukemia(AML) in patients with H/VH MDS treated with QHP(QHP group, n = 27) and decitabine(decitabine group, n = 20) were retrospectively analyzed. The effects of prognostic factors of age, proportion of bone marrow blast,peripheral blood cell count, karyotype and Charlson Comorbidity Index(CCI) on OS were further analyzed. RESULTS: The m OS rate of QHP group(29 months) was signi?cantly longer than that of the decitabine group(18 months)(P = 0.043). The OS rates of 1, 2, and 3 years were signi?cantly higher in the QHP group(88.9%, 59.3%, 29.6%) than that in the decitabine group(70%, 25%, and 5%)(P = 0.01). There was no signi?cant difference of 5-year OS rate between the 2 groups(P = 0.133).The effects of prognostic factors on mOS were further analyzed, and it was found that there was no signi?cant difference of m OS rate between the QHP group(29 months) and the decitabine group(21 months) in the patients with age 65 years old(P = 0.673). The mOS rate was signi?cantly longer in QHP group(28.5 months) than that in decitabine group(18 months) in the patients with age of < 65 years old(P = 0.04). The proportions of bone marrow blast cells with 10% or < 10% had no signi?cant effects on the mOS rate of patients in the 2 groups(P = 0.429, P = 0.183). In patients with HGB 80 g/L, mOS rate was signi?cantly longer in the QHP group(57 months) than that in the decitabine group(21 months)(P = 0.047), while in patients with HGB < 80 g/L, there was no signi?cant difference of mOS rate between the 2 groups(P = 0.265). In the patients with PLT < 50×10~9/L, the mOS rate was signi?cantly longer in the QHP group(33 months) than that in the decitabine group(16 months)(P = 0.028). In the patients with PLT 50×10~9/L, there was no signi?cant difference of the mOS rate between the 2 groups(P = 0.338). In the patients with ANC < 0.8×10~9/L, the mOS rate was signi?cantly longer in the QHP group(20 months) than that in the decitabine group(7 months)(P = 0.014). In the patients with normal karyotype, the mOS was signi?cantly longer in the QHP group(32 months) than that in the decitabine group(15 months)(P = 0.009). In the patients with abnormal karyotypes, there was no significant difference of the mOS rate between the 2 groups(P = 0.882). In the patients with good karyotypes, the mOS rate was signi?cantly longer in the QHP group(37 months) than that in the decitabine group(20 months)(P = 0.019). In the patients with moderate/poor/very poor karyotype, there was no signi?cant difference of the mOS rate between the 2 groups(P = 0.685). In the patients with CCI 3, the mOS rate was signi?cantly longer in the QHP group(34 months) than that in the decitabine group(10.5 months)(P = 0.017). In patients with CCI < 3, there was no signi?cant difference of the mOS rate between the 2 groups(P = 0.581). The proportion of progression to AML in the QHP group(18.8%) was signi?cantly lower than that in the decitabine group(25%)(P = 0.03). CONCLUSION: Compared with decitabine, oral administration of arsenic-containing Qinghuang Powder could help patients to survive longer and decrease incidence of progression to acute myeloid leukemia in the treatment of patients with high/very high MDS.

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.

BURDEN OF ABNORMAL HEMATOPOIETIC CLONE IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES

Objective To investigate the role of the burden of abnormal hematopoietic clone in the development of myelodysplastic syndromes (MDS). Methods The ratio of the bone marrow cells with abnormal chromosomes to the total counted bone marrow cells was regarded as the index of MDS clone burden. The disease severity related parameters including white blood cell count, hemoglobin, platelet count, lactate dehydrogenase level, bone marrow blast, myeloid differentiation index, micromegakaryocyte, transfusion, interleukin-2, tumor necrosis factor (TNF), CD4^+ and CD8^+ T cells of MDS patients were assayed, and the correlations between those parameters and MDS clone burden were also analyzed. Results The clone burden of MDS patients was 67.4%±36.2%. MDS clone burden positively correlated with bone marrow blasts (r = 0.483, P<0.05), negatively with hemoglobin level (r=-0.445, P<0.05). The number of blasts, hemoglobin, and erythrocytes in high clone burden (>50%) and low clone burden (≤50%) groups were 7.78%±5.51% and 3.45%±3.34%, 56.06±14.28 g/L and 76.40±24.44 g/L, (1.82±0.48)×10~ 12 /L and (2.32±0.66)×10~ 12 /L, respectively (all P<0.05). CD4^+ T lymphocytes of MDS patients and normal controls were (0.274±0.719)×10~ 9 /L and (0.455±0.206)×10~ 9 /L, respectively (P<0.05). CD8^+ T lymphocytes of MDS patients and normal controls were (0.240±0.150)×10~ 9 /L and (0.305±0.145)×10~ 9 /L, respectively. The serum level of interleukin-2 of MDS patients (6.29±3.58 ng/mL) was significantly higher than normal control (3.11±1.40 ng/mL, P<0.05). The serum level of TNF of MDS patients and normal control group were 2.42±1.79 ng/mL and 1.68±0.69 ng/mL, respectively. The ratio of CD4 to CD8 was higher in high clone burden MDS patients (1.90±0.52) than that in low clone burden patients (0.97±0.44, P<0.05). Conclusion The quantitive clonal karyotype abnormalities and deficient T cell immunity are important parameters for evaluating MDS severity and predicting its progression.

Expression of DLK1 Gene in the Bone Marrow Cells of Patients with Myelodysplastic Syndromes and Its Clinical Significance

Objective This study aims to investigate the expression of delta-like 1(DLKl) gene in the bone marrow cells of patients with myelodysplastic syndromes(MDS) and to explore its molecular characteristics for the early diagnosis of MDS. Methods The expression of DLK1 mRNA in the bone marrow cells of cases with MDS,acute myeloid leukemia(AML),and normal control groups were measured by real-time polymerase chain reaction and were analyzed for clinical significance. Results Significantly higher expression of DLK1 mRNA was observed in the bone marrow cells of MDS patients(0.7342±0.3652) compared with the normal control group(0.4801±0.1759)(P<0.05).The expression of DLK1 mRNA had a positive correlation with the proportion of bone marrow blasts(r=0.467,P<0.05).Moreover,DLKl mRNA expression was significantly increased as MDS progressed (P<0.05).Patients with abnormal karyotypes exhibited significantly higher expression of DLKl mRNA(0.9007±0.4334) than those with normal karyotypes(0.6411±0.2630)(P<0.05).Subsequently,patients with highly expressed DLKl(>0.8) presented significantly higher malignant clone burden(0.4134±0.3999) than those with lower DLKl expression(<0.8),(0.1517±0.3109),(P<0.05). Conclusions The DLK1 gene was highly expressed in MDS patients,and was increased as MDS progressed.The expression of DLK1 mRNA was positively correlated with the proportion of the bone marrow blasts.A high expression of DLKl gene suggested a higher malignant clone burden of MDS.

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.

Relapsing Polychondritis Associated with Myelodysplastic Syndrome

A 62-year-old man had arthritis and an infiltrated purpuric eruption of the legs. He presented then a cyanosis and aches of the left ear’s pinna with a voice disturbance and an inflammatory aspect of the nose. He had an anemia and a thrombopenia. The infectious and auto-immune research was negative. The laryngo-tracheal scan revealed calcifications of the larynx, the trachea and the initial portion of bronchi. Moreover, the biopsy from ear’s pinna cartilage confirmed the diagnosis of chondritis and peri-chondritis. He was thus considered to have the association with relapsing polychondritis and a myelodysplastic syndrome. The patient was treated with corticosteroids and iterative transfusions. The articular and skinny patient’s symptoms completely resolved. The anemia and the thrombopenia were partially improved. The relapsing polychondritis can be considered as paraneoplastic complication in the context of a myelodysplastic syndrome or as a fortuitous association. The mechanism of such an association remains unknown.

Decreased CD10-positive granulocytes for the differential diagnosis of myelodysplastic syndrome

Myelodysplastic syndromes(MDS)are highly heterogeneous myeloid neoplasms,and a large number of patients are difficult to diagnose and classify by blood and bone marrow examination.As a surface marker of granulocyte,studies have shown CD10 can be used to define the degree of granulocyte maturation in MDS patients.However,whether it can be used for differential diagnosis of MDS and other hematological diseases remains inconclusive.To explore the value of CD10 for differential diagnosis of MDS,60 newly diagnosed MDS,20 aplastic anemia(AA)patients,and 35 iron-deficient anemia(IDA)patients were selected for this study.Bone marrow(BM)specimens were processed for surface marker analysis and labeled with pre-conjugated monoclonal antibodies.Stained cells were detected by flow cytometry.Our results indicated that CD10-positive granulocytes were significantly decreased in BM of MDS patients than AA and IDA patients,and the level of CD10-positive mature granulocytes was not associated with the clinical stages of malignancy.Receiver operating characteristic(ROC)areas under the curve(AUC)of CD10-positive granulocytes was 0.86 and 0.85,respectively,in MDS patients than the IDA group and AA group with good specificity and sensitivity.Further,CD10-positive granulocytes were increased after effective treatment.In conclusion,we found the decrease in CD10-positive granulocytes has a differential diagnostic value of MDS.

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.