RESUMO
To identify the molecular signatures that predict responses to decitabine (DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response (CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post-DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine-induced complete responses in patients with MDS. DAC-induced responses may result from partial suppression of malignant clones containing mutated TP53 genes.
Assuntos
Azacitidina/análogos & derivados , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Proteína Supressora de Tumor p53/genética , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Transformação Celular Neoplásica/genética , Aberrações Cromossômicas , Decitabina , Humanos , Leucemia Mieloide Aguda/etiologia , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Valor Preditivo dos Testes , Recidiva , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoRESUMO
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.
Assuntos
Eritropoese , Síndromes Mielodisplásicas , Animais , Humanos , Camundongos , Eritropoese/genética , Síndromes Mielodisplásicas/genética , Proteínas do Tecido Nervoso/genética , Prognóstico , Receptores Imunológicos/genética , Proteínas RoundaboutRESUMO
We conducted a clinical trial of low-dose decitabine plus aclacinomycin/cytarabine (AA) treatment (DAA) for 20 patients with refractory/relapsed de novo acute myeloid leukemia (AML) or AML transformed from myelodysplastic syndrome (MDS/AML) in order to examine its efficacy and tolerability. Additionally, P15(ink4b) methylation status was analyzed (for 15 patients) pre- and post-DAA treatment, and in vitro drug sensitivity tests were performed for seven patients (AA or AA + decitabine) to explore the role of decitabine in this combination treatment regimen. A total of 11 patients (55.0 %) achieved complete remission (CR) after DAA treatment, including 7 of whom reached CR after only one treatment course. The other two patients achieved partial remission. The median overall survival (OS) was 10 months for all 20 patients. The median OS for those who achieved CR was significantly longer than that of patients with no response (NR; P = 0.01). The treatment regimen was well tolerated, and there was no treatment-related mortality. The mean levels of P15(ink4b) methylation decreased significantly in six patients who achieved CR, whereas very few changes in P15 (ink4b) methylation were detected for the five patients with NR following DAA treatment. The data from the methyl thiazolyl tetrazolium assays showed that the inhibition rates of AA and DAA for tumor cells were identical. We conclude that induction therapy with DAA for refractory/relapsed de novo AML or MDS/AML achieved high levels of CR and improved OS and demonstrated adequate tolerance. Moreover, the decitabine component of DAA may function through a demethylation effect.
Assuntos
Aclarubicina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/análogos & derivados , Citarabina/uso terapêutico , Metilases de Modificação do DNA/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda/tratamento farmacológico , Aclarubicina/administração & dosagem , Aclarubicina/efeitos adversos , Aclarubicina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Metilação de DNA/efeitos dos fármacos , Decitabina , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Análise de Sobrevida , Células Tumorais Cultivadas , Adulto JovemRESUMO
AIM: This study compared genetic aberrations in hematopoietic cells (HCs) and mesenchymal stem cells of myelodysplastic syndrome (MDS-MSCs) patients. METHODS: We obtained chromosomes with aberrations from 22 patients with MDS and chromosomes from 7 healthy individuals. Chromosomal aberrations in both HCs and MSCs were identified using G-banding. We then performed DNA content analysis of the HCs and MSCs. RESULTS: Cytogenetic aberrations were detected in HCs from 13 of the 22 MDS patients (59%). Chromosomal aberrations in MSCs were detected in 15 of the 22 MDS patients (68%). No chromosomal abnormalities were identified in MSCs of the 7 healthy volunteers. We demonstrate herein that MSCs have distinct genetic abnormalities compared to HCs from the same individual. We observed a random loss of chromosomal material in significant proportions of MSCs. A high proportion of random loss may be a marker of chromosomal instability of MDS-MSCs. However, two case results showed that HCs and MSCs have different altered structural changes. CONCLUSION: Our results suggest enhanced genetic susceptibility of these cells in MDS patients. Our data indicates that the genetic alterations in MSCs may constitute a particular biological mechanism of MDS pathogenesis.
Assuntos
Aberrações Cromossômicas , Células-Tronco Mesenquimais/patologia , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Fenótipo , Estudos ProspectivosRESUMO
Objective: To investigate the effect of iron overload (IO) on red blood cell (RBC) lifespan in MDS patients with the use of carbon monoxide breath test. Methods: The red blood cell lifespan of 93 patients with myelodysplastic syndrome (MDS) and 22 healthy volunteers in the control group were measured by alveolar gas carbon monoxide (CO) assay, with the detection of liver iron concentration, iron metabolism index, erythropoietin (EPO) concentration, peripheral blood inflammatory cytokines, etc. The MDS patients were divided into the severe IO group, mild IO group and non IO group according to liver iron concentration. The effect of IO on RBC lifespan was analyzed in MDS patients. Results: The RBC lifespan of MDS patients in the severe IO group was significantly lower than that in the mild IO group (p<0.05), while the RBC life span in the mild IO group was significantly lower than that in the non IO group (p<0.05). The expression of inflammatory cytokines in the severe IO group was significantly higher than that of the mild and non IO groups. After receiving iron removal treatment(ICT), the expression of inflammatory cytokines was decreased significantly, and the RBC lifespan was significantly prolonged (p<0.05).Besides, liver iron concentration was significantly positively correlated with EPO concentration, while EPO concentration was significantly negatively correlated with RBC lifespan, especially in the MDS-RS subgroup. The RBC lifespan in the EPO>1000 group was significantly lower than that in the EPO<1000 group. Conclusion: IO can shorten RBC lifespan in MDS patients, which may be result from the increase of endogenous EPO and the over-expression of inflammatory cytokines. After ICT, the ineffective hematopoiesis caused by increased EPO may reduced and the decrease of inflammatory cytokine may significantly prolong the RBC lifespan in MDS patients.
RESUMO
Objective: The purpose of this study was to identify the difference between dual energy spectral computed tomography (DECT) and magnetic resonance imaging (MRI) used to detect liver/cardiac iron content in Myelodysplastic syndrome (MDS) patients with differently adjusted serum ferritin (ASF) levels. Method: Liver and cardiac iron content were detected by DECT and MRI. Patients were divided into different subgroups according to the level of ASF. The receiver operating characteristic curve (ROC) analysis was applied in each subgroup. The correlation between iron content detected by DECT/MRI and ASF was analyzed in each subgroup. Result: ROC curves showed that liver virtual iron content (LVIC) Az was significantly less than liver iron concentration (LIC) Az in the subgroup with ASF < 1,000 ng/ml. There was no significant difference between LVIC Az and LIC Az in the subgroup with 1,000 ≤ ASF < 2,500 ng/ml and 2,500 ≤ ASF < 5,000 ng/ml. LVIC Az was significantly higher than LIC Az in the subgroup with ASF <5,000 and 5,000 ≤ ASF ng/ml. In patients undergoing DECT and MRI examination on the same day, ASF was significantly correlated with LVIC, whereas no significant correlation was observed between ASF and LIC. After removing the data of ASF > 5,000 mg/L in LIC, LIC became correlated with ASF. There was no significant difference between the subgroup with 2,500 ≤ ASF < 5,000 ng/ml and 5,000 ng/ml ≤ ASF in LIC expression. Furthermore, both LIC and liver VIC had significant correlations with ASF in patients with ASF < 2,500 ng/ml, while LVIC was still correlated with ASF, LIC was not correlated with ASF in patients with 2,500 ng/ml ≤ ASF. Moreover, neither cardiac VIC nor myocardial iron content (MIC) were correlated with ASF in these subgroups. Conclusion: MRI and DECT were complementary to each other in liver iron detection. In MDS patients with high iron content, such as ASF ≥ 5,000 ng/ml, DECT was more reliable than the MRI in the assessment of iron content. But in patients with low iron content, such as ASF < 1,000 ng/ml, MRI is more reliable than DECT. Therefore, for the sake of more accurately evaluating the iron content, the appropriate detection method can be selected according to ASF.
RESUMO
BACKGROUND: BCOR (BCL6 corepressor) is an epigenetic regulator gene involved in the specification of cell differentiation and body structure development. Recurrent somatic BCOR mutations have been identified in myelodysplastic syndrome (MDS). However, the clinical impact of BCOR mutations on MDS prognosis is controversial and the response of hypomethylating agents in MDS with BCOR mutations (BCORMUT) remains unknown. RESULTS: Among 676 MDS patients, 43 patients (6.4%) harbored BCOR mutations. A higher frequency of BCOR mutations (8.7%) was investigated in patients with normal chromosome, compared to 4.2% in patients with abnormal karyotype (p = 0.040). Compared to the BCORWT patients, the BCORMUT patients showed a higher ratio of refractory anemia with excess blasts subset (p = 0.008). The most common comutations with BCOR genes were ASXL1 (p = 0.002), DNMT3A (p = 0.114) and TET2 (p = 0.148). When the hierarchy of somatic mutations was analyzed, BCOR mutations were below the known initial mutations (ASXL1 or TET2) but were above U2AF1 mutations. Transformation-free survival was significantly shorter in BCORMUT patients than that in BCORWT patients (16 vs. 35 months; p = 0.035). RNA-sequencing was performed in bone marrow mononuclear cells from BCORMUT and BCORWT patients and revealed 2030 upregulated and 772 downregulated genes. Importantly, HOXA6, HOXB7, and HOXB9 were significantly over-expressed in BCORMUT patients, compared to BCORWT patients. Eight of 14 BCORMUT patients (57.1%) achieved complete remission (CR) with decitabine treatment, which was much higher than that in BCORWT patients (28.7%, p = 0.036). Paired sequencing results (before and after decitabine) showed three of 6 CR patients lost the mutated BCOR. The median survival of CR patients with a BCORMUT was 40 months, which was significantly longer than that in patients with BCORWT (20 months, p = 0.036). Notably, prolonged survival was observed in three BCORMUT CR patients even without any subsequent therapies. CONCLUSIONS: BCOR mutations occur more frequently in CN MDS patients, predicting higher risk of leukemia transformation. BCORMUT patients showed a better response to decitabine and achieved longer post-CR survival.
Assuntos
Metilação de DNA/genética , Epigênese Genética , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/fisiopatologia , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Regulação da Expressão Gênica , Variação Genética , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
OBJECTIVES: We aim to explore and analyze the related influencing factors of liver and cardiac iron overload in MDS patients detected by magnetic resonance imaging (MRI). METHODS: We have detected cardiac T2* and liver T2* by MRI in 105 MDS patients. Among them, 20 patients accepted MRI examination before and after iron chelation therapy (ICT). Results: We found that adjusted ferritin (ASF) was significantly correlated with liver T2* and cardiac T2*. RBC transfusion volume, brain natriuretic peptide (BNP) and age were the related factors of cardiac T2*, while RBC transfusion volume and erythropoietin (EPO) were related factors of liver T2*. After ICT, the changes of ASF and liver T2* were earlier than cardiac T2*. Chronic hepatitis but virus copy normal's has no significant effect on liver iron deposition. CONCLUSION: These results showed special attention should be paid to these related influencing factors of liver and cardiac T2* expression when we evaluated iron overload and detected the efficacy of ICT in MDS patients.
Assuntos
Coração/diagnóstico por imagem , Sobrecarga de Ferro/diagnóstico por imagem , Sobrecarga de Ferro/etiologia , Fígado/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Eritrócitos , Feminino , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/patologia , Sobrecarga de Ferro/terapia , Fígado/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Fatores de Risco , Adulto JovemRESUMO
Decitabine (DAC) is considered to be a profound global DNA demethylation, which can induce the re-expression of silenced tumor suppressor genes. Little is known about the function of tumor suppressor gene FOXO1 in myelodysplastic syndromes (MDS). To address this issue, the study firstly investigated differentially expressed genes (DEGs) for DAC treatment in MDS cell lines, then explored the role of FOXO1 through silencing its expression before DAC treatment in MDS. The results showed that FOXO1 exists in a hyperphosphorylated, inactive form in MDS-L cells. DAC treatment both induces FOXO1 expression and reactivates the protein in its low phosphorylation level. Additionally, the results also demonstrated that this FOXO1 activation is responsible for the DAC-induced apoptosis, cell cycle arrest, antigen differentiation, and immunoregulation in MDS-L cells. We also demonstrated DAC-induced FOXO1 activation upregulates anti-tumor immune response in higher-risk MDS specimens. Collectively, these results suggest that DAC induces FOXO1 activation, which plays an important role in anti-MDS tumors.
RESUMO
Despite the improvements in prognostication of the revised International Prognostic Scoring System (IPSS-R) in myelodysplastic syndrome (MDS), there remain a portion of patients with lower risk (low/intermediate risk, LR) but poor prognostics. This study aimed to evaluate the relative contribution of mutational status when added to the IPSS-R, for estimating overall survival (OS) and progression-free survival (PFS) in patients with LR-MDS. We retrospectively analyzed clinical and laboratory variables of 328 patients diagnosed with MDS according to the FAB criteria. Twenty-nine-gene NGS assay was applied to bone marrow samples obtained at diagnosis. 233 (71.04%) patients were classified as LR-MDS. Univariate analysis showed association between inferior outcome (OS and PFS) and presence of JAK2 (p = 0.0177, p = 0.0002), RUNX1 (p = 0.0250, p = 0.0387), and U2AF1 (p = 0.0227, p = 0.7995) mutations. Multivariable survival analysis revealed JAK2 (p < 0.0001) and RUNX1 (p = 0.0215) mutations were independently prognostic for PFS in LR-MDS. Interestingly, bone marrow blast >1.5% could further predict disease progression of patients with LR-MDS (HR 8.06, 95%CI 2.95-22.04, p < 0.0001). Incorporation of JAK2, RUNX1 mutation and bone marrow blast in the IPSS-R can improve risk stratification in patients with LR-MDS. In summary, our result provided new risk factors for LR-MDS prognostics to identify candidates for early therapeutic intervention.
RESUMO
Erythroid apoptosis increases significantly in myelodysplastic syndrome (MDS) patients with iron overload, but the underlying mechanism is not fully clear. In this study, we aim to explore the effect of HIF-1a/ROS on erythroid apoptosis in MDS patients with iron overload. We found that iron overload injured cellular functions through up-regulating ROS levels in MDS/AML cells, including inhibited cell viability, increased cell apoptosis and blocked cell cycle at G0/G1 phase. Interestingly, overexpression of hypoxia inducible factor-1a (HIF-1a), which was under-expressed in iron overload models, reduced ROS levels and attenuated cell damage caused by iron overload in MDS/AML cells. And gene knockdown of HIF-1a got the similar results as iron overload in MDS/AML cells. Furthermore, iron overload caused high erythroid apoptosis was closely related with ROS in MDS patients. Importantly, the HIF-1a protein levels of erythrocytes elevated obviously after incubation with desferrioxamine (DFO) from MDS patients with iron overload, accompanied by ROS levels inhibited and erythroid apoptosis reduced. Taken together, our findings determine that the HIF-1a/ROS signaling pathway plays a key role in promoting erythroid apoptosis in MDS patients with iron overload.
Assuntos
Eritrócitos/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sobrecarga de Ferro/complicações , Síndromes Mielodisplásicas/complicações , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/fisiologia , Western Blotting , Feminino , Citometria de Fluxo , Humanos , Sobrecarga de Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/fisiologiaRESUMO
Decitabine is an effective therapy for patients with lower risk myelodysplastic syndrome (MDS). However, the mechanisms of decitabine's therapeutic effect are not well established. Forty-four lower risk MDS patients received decitabine therapy. 59.1% patients achieved treatment response, and 53.8% patients who were RBC/platelet-dependent cast off the transfusion burden. The median overall survival (OS) was 19.0 months after decitabine treatment. Moreover, polarization toward type 1 in the CD8 + subset was enhanced, and a significantly increased expression of the PD-1, PD-L1, and PD-1/STAT1 ratio was observed in these lower risk MDS. The patients with amplification of PD-1/STAT1 ratio (2-4) achieved longer OS. Thus, our results suggest that the effect mechanism of decitabine toward lower risk MDS may be the moderate increase of PD-1/STAT1, which contributes to hematopoietic improvement. These findings suggest that a different PD-1-related strategy from those used to treat higher risk patients could be used for lower risk MDS patients.
Assuntos
Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/mortalidade , Receptor de Morte Celular Programada 1/metabolismo , Fator de Transcrição STAT1/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores , Relação CD4-CD8 , Decitabina , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/genética , Modelos de Riscos Proporcionais , Fator de Transcrição STAT1/genética , Linfócitos T/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
Novel sequencing designs are necessary to supplement the recognized knowledge of myelodysplastic syndrome (MDS)-related genomic alterations. In this study, we sequenced 28 target genes in 320 Chinese MDS patients but obtained 77.2% of recall factors and 82.8% of genetic abnormalities (including karyotype abnormalities). In addition to known relationships among mutations, some specific chromosomal abnormalities were found to link to specific gene mutations. Trisomy 8 tended to be linked to U2AF1 and ZRSR2 mutations, and 20q- exhibited higher SRSF2/WT1 and U2AF1 mutation frequency. Chromosome 7 involvement accounted for up to 50% of RUNX1 mutations and 37.5% of SETBP1 mutations. Patients carrying a complex karyotype were prone to present TP53 mutations (36.1%). However, individuals with normal karyotypes rarely possessed mutations in the TP53, RUNX1 and U2AF1. Moreover, DNMT3A, TP53, SRSF2, STAG2, ROBO1/2 and WT1 predicted poor survival and high AML transformation. By integrating these predictors into international prognostic scoring system (IPSS) or revised IPSS, we built a set of mutation-based prognostic risk models. These models could layer different degrees of risk in patients more satisfactorily. In summary, this sequencing design was able to detect a number of gene mutations and could be used to stratify patients with varied prognostic risk.
Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático/genética , Criança , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Decitabine treatment improves immunological recognition that increases expression of cancer-testis antigens (CTAs) against solid tumors. The mechanisms of decitabine enhancement of immunogenicity when used for patients with myelodysplastic syndromes (MDS) remain unclear. In the present study, we found relatively low baseline expression of MAGE-A1, MAGE-A3, and SP17 in MDS-derived cell lines. Decitabine treatment significantly improved MAGE-A1, MAGE-A3, and SP17 expression in these cell lines and in MDS patients. Decitabine-treated K562 and SKM-1 target cells with incrementally induced MAGE-A1, MAGE-A3, or SP17 levels up-regulated T lymphocyte function. Decitabine treatment improved CTA-specific cytotoxic T lymphocyte (CTL) recognition of MDS cells via the up-regulation of CTAs. This response was accompanied by enhanced T lymphocyte function and HLA class antigen expression, and increased ICAM-1. These findings suggested that decitabine may have a broad range of therapeutic applications when it is used in association with active adaptive immunity responses against up-regulated CTAs.
Assuntos
Exame de Medula Óssea/métodos , Neoplasias da Medula Óssea/secundário , Medula Óssea/patologia , Neoplasias Pulmonares/patologia , Neoplasias Gástricas/patologia , Biópsia , Biópsia por Agulha , Neoplasias da Medula Óssea/patologia , Neoplasias da Mama/patologia , Técnicas Citológicas , Feminino , Humanos , Masculino , Neoplasias da Próstata/patologia , Estudos RetrospectivosRESUMO
The progressive mechanism underlying myelodysplastic syndrome remains unknown. Here we identify ROBO1 and ROBO2 as novel progression-related somatic mutations using whole-exome and targeted sequencing in 6 of 16 (37.5%) paired MDS patients with disease progression. Further deep sequencing detects 20 (10.4%) patients with ROBO mutations in a cohort of 193 MDS patients. In addition, copy number loss and loss of heterogeneity (LOH) of ROBO1 and ROBO2 are frequently observed in patients with progression or carrying ROBO mutations. In in vitro experiments, overexpression of ROBO1 or ROBO2 produces anti-proliferative and pro-apoptotic effects in leukaemia cells. However, this effect was lost in ROBO mutants and ROBO-SLIT2 signalling is impaired. Multivariate analysis shows that ROBO mutations are independent factors for predicting poor survival. These findings demonstrate a novel contribution of ROBO mutations to the pathogenesis of MDS and highlight a key role for ROBO-SLIT2 signalling in MDS disease progression.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Síndromes Mielodisplásicas/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/genética , Idoso , Western Blotting , Linhagem Celular Tumoral , Ensaio de Unidades Formadoras de Colônias , Progressão da Doença , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Transdução de Sinais , Proteínas RoundaboutRESUMO
Cerebral venous and sinus thrombosis is a rare cerebrovascular disorder, which seldom represents a complication of acute promyelocytic leukemia (APL). As a part of the coagulopathy of APL, thrombosis is a less recognized and underestimated life-threatening manifestation and is overshadowed by the more obvious bleeding complications. Here, we described a 28-year-old woman with APL who developed massive thrombosis of the cerebral sinuses while on induction treatment with all-trans retinoic acid. On the basis of this report, the potential pathogenic mechanisms and the diagnosis based on magnetic resonance imaging (MRI) combined with magnetic resonance venogram (MRV) are discussed. Early anticoagulant therapy contributed to the progressive dissolution of the thrombosis, as documented by MRI, with the complete disappearance of neurological signs without sequelae. Given the increasing recognition of thromboembolic events in APL, the use of prophylactic anticoagulation during induction therapy may need to be redefined.
Assuntos
Leucemia Promielocítica Aguda/complicações , Trombose dos Seios Intracranianos/etiologia , Tretinoína/uso terapêutico , Adulto , Anticoagulantes/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Trombose dos Seios Intracranianos/prevenção & controle , Tretinoína/efeitos adversosRESUMO
Abnormal immunophenotypes of hematopoietic cells can be detected by flow cytometry (FCM) to assist the diagnosis of myelodysplastic syndromes (MDS). We previously established a FCM scoring system for the diagnosis of low-grade MDS. In this study, additional valuable antigens were involved in an updated FCM scoring system (u-FCMSS) for all MDS subtypes. The u-FCMSS showed better sensitivity and specificity (89.4% and 96.5%) in distinguishing MDS from non-clonal cytopenia diseases. Validation analysis of u-FCMSS exhibited comparable sensitivity and specificity (86.7% and 93.3%) and high agreement rate (88.9%) of FCM diagnosis with morphological diagnosis at optimal cut-off (score 3). The distribution of FCM scores in different disease stages was also analyzed. The results suggested that early scoring from abnormal expression of mature myeloid/lymphoid antigens and advanced scoring from abnormal expression of stem/progenitor antigens expression constituted the majority of FCM scores of low-grade and high-grade MDS, respectively. High early scoring was generally accompanied by low IPSS-R score and superior survival, whereas high advanced scoring was accompanied by high IPSS-R score and inferior survival. In addition, the low-risk MDS patients with high early scoring and low advanced scoring were revealed as candidates for immunosuppressive therapy, whereas those with high advanced scoring and low early scoring may be more suitable for decitabine treatment. In conclusion, the u-FCMSS is a useful tool for diagnosis, prognosis and treatment selection in MDS. Differences in classes of antigens expressed and in distribution of FCM scores may reflect distinctive stage characteristics of MDS during disease progression.
Assuntos
Antígenos CD34/metabolismo , Citometria de Fluxo/métodos , Imunofenotipagem/métodos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue , Estudos de Coortes , Progressão da Doença , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Prognóstico , Células-Tronco/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this study was to investigate the tissue factor (TF) expression of platelets and leukocytes in patients with acute coronary syndrome (ACS), patients with stable angina (SA) and healthy subjects (as controls). 26 patients with ACS, 29 patients with SA, and 25 controls were enrolled in this study. The peripheral blood samples of above-mentioned subjects were collected and isolated to obtain the monocytes and platelet-rich plasma, the TF-mRNA expression of monocytes, and platelets among 3 groups was detected by RT-PCR, the TF expression ratio of platelets, platelet-leukocyte aggregates (PLA) and platelet-monocyte aggregates (PMP) was detected by flow cytometry among 3 groups. The results showed that the TF mRNA expression level of platelets in ACS group were significantly higher (3.11 ± 0.51 relative expression) as compared with SA and control groups (1.88 ± 0.78 and 0.7 ± 0.1, respectively) (P = 0.03). Expression of TF mRNA of monocytes was higher in ACS group (P = 0.05 versus controls) too. ACS group had a significantly higher amount of TF-positive platelets (8.8 ± 2.6) than SA (2.6 ± 0.5, P = 0.02) or control groups (2.5 ± 0.4, P = 0.02). A significantly greater number of TF positive platelet-leukocyte aggregates and platelet-monocyte aggregates were also found by flow cytometry in blood of ACS patients than in either SA patients or controls. It is concluded that the high TF expression of platelets and leukocytes in ACS patients strengthens the platelet activation, blood coagulation, and thrombus formation and may further contribute to the hypercoagulability associated with the disease. The present study further extends the proinflammatory/prothrombotic phenotype of ACS patients showing that new players on the scene.
Assuntos
Síndrome Coronariana Aguda/sangue , Angina Estável/sangue , Plaquetas/metabolismo , Leucócitos/metabolismo , Tromboplastina/metabolismo , Idoso , Estudos de Casos e Controles , Adesão Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária , RNA Mensageiro/metabolismoRESUMO
OBJECTIVE: To detect p15(INK4B) methylation levels and the kinetics of the methylation status before and after decitabine to explore its influences on prognosis and response to decitabine in myelodysplastic syndromes (MDS) patients. METHODS: We examined 261 MDS patients (143 male and 118 female) with the median age of 52 years (32-78). Of them, 172 cases were low-risk group (low-risk 104 cases, intermediate-1 68 cases), 89 cases high-risk group (intermediate-2 52 cases, high risk 37 cases). Collections of bone marrow mononuclear cells of MDS patients and extracted the genomic DNA, the methylation status of p15(INK4B) was detected by methylation-specific PCR (MSP) method. Survival analysis was conducted according to the level of p15(INK4B) methylation in the cohort of patients. The kinetics of the methylation levels of p15(INK4B) in 58 MDS patients before and after 2 courses of decitabine have been assessed with the method of MSP. RESULTS: The methylation level of p15(INK4B) in low-risk group patients was significantly lower than that in high-risk group (117.22 vs 157.63, P<0.05 ). The expected 2-year survival rate of p15(INK4B) methylation positive patients was lower than that of negative ones (91.8% vs 69.8%, P<0.05); the expected 2-year survival rate of p15(INK4B) methylation positive patients was shorter than that of negative ones in low-risk groupï¼78.2% vs 92.0%, P<0.05ï¼, meanwhile there was no significant difference in terms of expected 2-year survival rate and median expected survival between p15(INK4B) methylation positive and negative patients in high-risk group [35.6% vs 38.5%, (17.0±9.3) month vs (18.0±5.7) month, P>0.05]. Multivariate analysis showed p15(INK4B) methylation degree was an independent prognostic factor for overall survival. No statistical difference of overall response (OR) rates were found between p15(INK4B) methylation positive patients and negative patients before decitabineï¼65.9% vs 76.5%, P>0.05ï¼, and complete remission (CR) rates between these two groups also showed no statistical differenceï¼22.0% vs 29.4%, P>0.05ï¼. p15(INK4B) methylation levels had no obvious change before and after treatment in decitabine respondersï¼P>0.05ï¼. CONCLUSION: The survival of newly diagnosed MDS patients with positive p15(INK4B) methylation was comparatively shorter, but p15(INK4B) methylation had no influence on response to decitabine.