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1.
Blood ; 135(1): 41-55, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31697823

RESUMO

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.

2.
Br J Haematol ; 187(2): 227-237, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31206607

RESUMO

The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%-91%) vs. 91% (95% CI, 82%-96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.

3.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(11): 958-963, 2018 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-30477631

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare chronic myeloid leukemia in children and has the features of both myelodysplastic syndrome and myeloproliferative neoplasm. It is highly malignant and has a poor treatment outcome. Children with JMML have a poor response to conventional chemotherapy. At present, hematopoietic stem cell transplantation is the only possible cure for this disease. In recent years, significant progress has been made in targeted therapy for mutant genes in the Ras signaling pathway and demethylation treatment of aberrant methylation of polygenic CpG islands. This article reviews the treatment and efficacy evaluation of JMML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Juvenil , Síndromes Mielodisplásicas , Criança , Humanos , Metilação , Transdução de Sinais
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(10): 819-824, 2018 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-30369356

RESUMO

OBJECTIVE: To investigate the value of multiparameter flow cytometry (MFC) and flow cytometric scoring system (FCSS) in the diagnosis and prognostic evaluation of childhood myelodysplastic syndrome (MDS). METHODS: A retrospective analysis was performed for the clinical data of 42 children who were diagnosed with MDS. MFC was performed to investigate the phenotype and proportion of each lineage of bone marrow cells. The correlations of FCSS score with MDS type, International Prognostic Scoring System (IPSS) score, and revised IPSS (IPSS-R) score were analyzed. RESULTS: Of all the 42 children, 20 (48%) had an increase in abnormal marrow blasts, 19 (45%) had a lymphoid/myeloid ratio of >1, 14 (33%) had abnormal cross-lineage expression of lymphoid antigens in myeloid cells, 8 (19%) had abnormal CD13/CD16 differentiation antigens, 5 (12%) had abnormal expression of CD56, 3 (7%) had reduced or increased side scatter of granulocytes, 3 (7%) had reduced expression of CD36 in nucleated red blood cells, 2 (5%) had reduced expression of CD71 in nucleated red blood cells, 1 (2%) had absent expression of CD33 in myeloid cells, 1 (2%) had reduced or absent expression of CD11b in granulocytes, and 1 (2%) had absent expression of CD56 and CD14 in monocytes. There were significant differences in the median overall survival time and event-free survival time among the low-, medium-, and high-risk FCSS groups (P<0.05). Among the low-, medium-, and high-risk FCSS groups, the low-risk FCSS group had the highest 2-year overall survival rate, while there was no significant difference between the medium- and high-risk FCSS groups (P>0.05). The three groups had a 2-year event-free survival rate of 95%, 60%, and 46% respectively (P<0.05). FCSS score was positively correlated with MDS type, IPSS score, and IPSS-R score (P<0.05). CONCLUSIONS: MFC and FCSS help with the diagnosis and prognostic evaluation of childhood MDS.


Assuntos
Síndromes Mielodisplásicas , Medula Óssea , Criança , Citometria de Fluxo , Humanos , Prognóstico , Estudos Retrospectivos
6.
Cell Signal ; 50: 72-79, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29964149

RESUMO

Constitutively activated MAPK and AKT signaling pathways are often found in solid tumors and leukemias. PTEN is one of the tumor suppressors that are frequently found deficient in patients with late-stage cancers or leukemias. In this study we demonstrate that a MAPK inhibitor, PD98059, inhibits both AKT and ERK phosphorylation in a human myeloid leukemia cell line (TF-1), but not in PTEN-deficient leukemia cells (TF-1a). Ectopic expression of wild-type PTEN in myeloid leukemia cells restored cytokine responsiveness at physiological concentrations of GM-CSF (<0.02 ng/mL) and significantly improved cell sensitivity to MAPK inhibitor. We also found that Early Growth Response 1 (EGR1) was constitutively over-expressed in cytokine-independent TF-1a cells, and ectopic expression of PTEN down-regulated EGR1 expression and restored dynamics of EGR1 expression in response to GM-CSF stimulation. Data from primary bone marrow cells from mice with Pten deletion further supports that PTEN is indispensible for myeloid leukemia cells in response to MAPK inhibitors. Finally, We demonstrate that the absence of EGR1 expression dynamics in response to GM-CSF stimulation is one of the mechanisms underlying drug resistance to MAPK inhibitors in leukemia cells with PTEN deficiency. Our data suggest a novel mechanism of PTEN in regulating expression of EGR1 in hematopoietic cells in response to cytokine stimulation. In conclusion, this study demonstrates that PTEN is dispensable for myeloid leukemia cells in response to MAPK inhibitors, and PTEN regulates EGR1 expression and contributes to the cytokine sensitivity in leukemia cells.


Assuntos
Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/metabolismo , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , PTEN Fosfo-Hidrolase/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Linhagem Celular , Regulação para Baixo/efeitos dos fármacos , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Células HEK293 , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Blood ; 131(20): 2256-2261, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29434033

RESUMO

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ∼10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB-rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1-PDGFRB, and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRBC843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB-mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inibidores de Proteínas Quinases/farmacologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Proteínas Angiogênicas/genética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Pré-Escolar , Humanos , Masculino , Proteínas de Fusão Oncogênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Resultado do Tratamento , Sequenciamento Completo do Genoma
8.
Leuk Res ; 65: 20-24, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29253671

RESUMO

Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Sequenciamento Completo do Exoma , Criança , China , Humanos , Leucemia Mieloide Aguda/etnologia
9.
Genomics Proteomics Bioinformatics ; 15(1): 37-48, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28185911

RESUMO

Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder in human bone marrow. Over 50% of patients with myelofibrosis have mutations in JAK2, MPL, or CALR. However, these mutations are rarely detected in children, suggesting a difference in the pathogenesis of childhood PMF. In this study, we investigated the response to drug treatment of a monozygotic twin pair with typical childhood PMF. The twin exhibited different clinical outcomes despite following the same treatment regimen. The transcriptomic profiles of patient samples after drug treatment (E2 and Y2) were significantly different between the twin pair, which is consistent with the observation that the drug treatment was effective only in the younger brother, despite the twin being genetically identical. Bioinformatics analysis of the drug-responsive genes showed that the JAK-STAT pathway was activated in the cured younger brother, which is opposite to the pathway inhibition observed in adult PMF cases following treatment. Moreover, apoptosis and cell cycle processes were both significantly influenced by drug treatment in the sample of younger brother (Y2), implying their potential association with the pathogenesis of childhood PMF. Gene mutations in JAK2, MPL, or CALR were not observed; however, mutations in genes including SRSF2 and SF3B1 occurred in this twin pair with childhood PMF. Gene fusion events were extensively screened in the twin pair samples and the occurrence of IGLV2-14-IGLL5 gene fusion was confirmed. The current study reported at transcriptomic level the different responses of monozygotic twin brothers with childhood PMF to the same androgen/prednisone treatment regimen providing new insights into the potential pathogenesis of childhood PMF for further research and clinical applications.


Assuntos
Mielofibrose Primária/patologia , Androgênios/uso terapêutico , Medula Óssea/patologia , Pré-Escolar , Cromossomos Humanos Par 19 , Análise Citogenética , Perfilação da Expressão Gênica , Fusão Gênica , Humanos , Cadeias lambda de Imunoglobulina/genética , Masculino , Mutação de Sentido Incorreto , Fosfoproteínas/genética , Prednisona/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , RNA/química , RNA/isolamento & purificação , RNA/metabolismo , Fatores de Processamento de RNA/genética , Análise de Sequência de RNA , Fatores de Processamento de Serina-Arginina/genética , Gêmeos Monozigóticos
10.
Zhongguo Dang Dai Er Ke Za Zhi ; 19(1): 27-33, 2017 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-28100318

RESUMO

OBJECTIVE: To evaluate the clinical characteristics and risk factors of clonal evolution after immunosuppressive therapy (IST) in children with severe/very severe aplastic anemia (SAA/VSAA). METHODS: The clinical data of 231 children with newly-diagnosed SAA/VSAA who received IST were retrospectively studied. The incidence and risk factors of clonal evolution after IST were analyzed. RESULTS: The 5-year overall survival rate of the 231 patients was 82.7%. Except for 18 cases of early deaths, 213 patients were evaluated for IST efficacy. Among the 231 patients, cytogenetic abnormalities for at least two chromosome metaphase were detectable in 14 (7.4%) patients, and PNH clones were detectable in either peripheral red blood cells or neutrophils for 95 patients. Among the 213 patients evaluated for IST efficacy, 15 patients experienced clonal evolution after IST. Five patients had PNH and trisomy 8 which were defined as favorable progressions, and ten patients experienced monosomy 7 and MDS/AML as unfavorable progressions. The 5-year accumulative incidence of favorable and unfavorable progression were (2.2±2.2)% and (4.8±3.3)%, respectively. Until the last follow-up, 100% (5/5) of patients with favorable progressions and 50% (5/10) of patients with unfavorable progressions survived. WBC>3.5×109/L, CD3+T cell percentage>80%, dosage of antithymocyte globulin >3.0 mg/(kg·d) and no response to IST were related to unfavorable progressions by univariate analysis. Cox multivariate analysis revealed that an increased CD3+T cell percentage (>80%) and no response to IST were independent risk factors for unfavorable progressions. CONCLUSIONS: The children with SAA/VSAA who have an increased CD3+T cell percentage at diagnosis or have no response to IST are in high risks of unfavorable progressions.


Assuntos
Anemia Aplástica/tratamento farmacológico , Evolução Clonal , Imunossupressores/uso terapêutico , Adolescente , Anemia Aplástica/genética , Anemia Aplástica/imunologia , Anemia Aplástica/mortalidade , Criança , Pré-Escolar , Aberrações Cromossômicas , Feminino , Humanos , Lactente , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos
11.
Nucleic Acids Res ; 45(2): 657-671, 2017 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-28123038

RESUMO

The first intronic mutations in the intron 1 GATA site (int-1-GATA) of 5-aminolevulinate synthase 2 (ALAS2) have been identified in X-linked sideroblastic anemia (XLSA) pedigrees, strongly suggesting it could be causal mutations of XLSA. However, the function of this int-1-GATA site during in vivo development remains largely unknown. Here, we generated mice lacking a 13 bp fragment, including this int-1-GATA site (T AGATAA: AGCCCC) and found that hemizygous deletion led to an embryonic lethal phenotype due to severe anemia resulting from a lack of ALAS2 expression, indicating that this non-coding sequence is indispensable for ALAS2 expression in vivo Further analyses revealed that this int-1-GATA site anchored the GATA site in intron 8 (int-8-GATA) and the proximal promoter, forming a long-range loop to enhance ALAS2 expression by an enhancer complex including GATA1, TAL1, LMO2, LDB1 and Pol II at least, in erythroid cells. However, compared with the int-8-GATA site, the int-1-GATA site is more essential for regulating ALAS2 expression through CRISPR/Cas9-mediated site-specific deletion. Therefore, the int-1-GATA site could serve as a valuable site for diagnosing XLSA in cases with unknown mutations.


Assuntos
5-Aminolevulinato Sintetase/genética , Sítios de Ligação , Diferenciação Celular , Células Eritroides/citologia , Células Eritroides/metabolismo , Fator de Transcrição GATA1/metabolismo , Íntrons , Anemia Sideroblástica/genética , Animais , Sequência de Bases , Sistemas CRISPR-Cas , Modelos Animais de Doenças , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica , Genes Letais , Doenças Genéticas Ligadas ao Cromossomo X/genética , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Hemizigoto , Humanos , Células K562 , Masculino , Mutação , Linhagem , Regiões Promotoras Genéticas , Deleção de Sequência
12.
Int J Hematol ; 104(4): 430-9, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27329125

RESUMO

Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by a paucity of erythroid progenitors. We summarized the clinical and genetic features of 104 DBA patients in a single-center retrospective study in China. Data of DBA patients who received consultations at our center from 2003 to 2015 were analyzed retrospectively. Genes encoding 10 ribosomal proteins (RPs) and GATA1 were sequenced for mutation detection. Our cohort was composed of 65 males and 39 females. Congenital malformations were observed in 19 patients. Mutations of the RP genes were detected in 58.3 % patients. Twenty different mutations were first reported. Thirty-four patients received prednisone combined with CsA therapy, and improvement was observed in 20 cases. During follow-up for a median 39 months, 33.7 % of the patients achieved remission, 41.3 % of the patients were persistently transfusion independent, 21.7 % of the patients were transfusion dependent, and three patients died. The patient group with detected mutations had a younger age of disease onset, a higher malformation rate, and tended to have a lower remission rate and a higher transfusion-dependence rate. Prednisone in combination with cyclosporine A can be a second-line choice for DBA patients. Differences were detected between DBA patients with and without detectable mutations in the genes studied.


Assuntos
Anemia de Diamond-Blackfan/genética , Mutação , Idade de Início , Anemia de Diamond-Blackfan/terapia , Transfusão de Sangue , China , Quimioterapia Combinada , Feminino , Humanos , Masculino , Estudos Retrospectivos , Proteínas Ribossômicas/genética , Resultado do Tratamento
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 23(3): 642-6, 2015 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-26117009

RESUMO

OBJECTIVE: To ovaluate the prognostic value of prednisone response in treatment regimes of children with acute lymphoblastic leukemia. METHODS: A total of 598 newly diagnosed ALL patients were enrolled and received prednisone pre-treatment. Based on the peripheral lymphoblast count on day 8, these patients were divided into 2 groups: prednisone good response (PGR) and prednisone poor response (PPR). PPR patients were classified into high risk group immediately and then received intensed chemotherapy. The all enrolled patients were followed up and the clinical features and treatment outcomes of the two groups were analyzed. RESULTS: Compared with PGR group, PPR group had different characteristics. They were older in age and had higher initial white blood cell count (P<0.05). T-cell ALL (T-ALL) and Philadelphia chromosome positive ALL (Ph+ ALL) were frequent in PPR group (P<0.05). Event-free survival (EFS) rate of PPR group was significantly lower than that of PGR group (P<0.05). 2 year event-free survival(EFS) rate of PGR group was (88.3±1.5)%, while the 2-year EFS rate of PPR group was (58.4±5.3)%. 5 year EFS rates of PGR and PPR were (80.8±2.1)% and (53.4±6.0)%, respectively. The EFS rate of PPR group was falling rapidly within 2 years. PPR group had higher relapse rate, and most relapses occurred within 18 months (P<0.05). PPR group had more high incidence of minimal residual disease (MRD) both on day 33 and on week 12 (P<0.05). No significant difference of EFS and relapse time was found between PPR and high risk PGR patients (P>0.05). In multi-variate regression analysis, the PPR, the presence of BCR-ABL1 and MLL were significantly unfavorable factors (P<0.05). CONCLUSION: Prednisone response has been confirmed to be still great prognostic value and PPR children patients have poor outcomes generally. It is likely that the response to prednisone does not make much sense to high risk ALL patients.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras , Intervalo Livre de Doença , Humanos , Análise Multivariada , Neoplasia Residual , Prednisona , Prognóstico , Recidiva , Resultado do Tratamento
14.
J Hematol Oncol ; 8: 55, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25985931

RESUMO

BACKGROUND: Congenital sideroblastic anemias (CSAs) comprise a group of heterogenous genetic diseases that are caused by the mutation of various genes involved in heme biosynthesis, iron-sulfur cluster biogenesis, or mitochondrial solute transport or metabolism. However, approximately 40% of patients with CSA have not been found to have pathogenic gene mutations. In this study, we systematically analyzed the mutation profile in 10 Chinese patients with sporadic CSA. FINDINGS: We performed targeted deep sequencing analysis in ten patients with CSA using a panel of 417 genes that included known CSA-related genes. Mitochondrial genomes were analyzed using next-generation sequencing with a mitochondria enrichment kit and the HiSeq2000 sequencing platform. The results were confirmed by Sanger sequencing. The ALAS2 mutation was detected in one patient. SLC25A38 mutations were detected in three patients, including three novel mutations. Mitochondrial DNA deletions were detected in two patients. No disease-causing mutations were detected in four patients. CONCLUSION: To our knowledge, the pyridoxine-effective mutation C471Y of ALAS2, the compound heterozygous mutation W87X, I143Pfs146X, and the homozygous mutation R134C of SLC25A38 were found for the first time. Our findings add to the number of reported cases of this rare disease and to the CSA pathogenic mutation database. Our findings expand the phenotypic profile of mitochondrial DNA deletion mutations. This work also demonstrates the application of a congenital blood disease assay and targeted capture sequencing for the genetic screening analysis and diagnosis of heterogenous genetic CSA.


Assuntos
Anemia Sideroblástica/genética , Análise Mutacional de DNA/métodos , Doenças Genéticas Ligadas ao Cromossomo X/genética , Biologia Molecular/métodos , Adolescente , Grupo com Ancestrais do Continente Asiático , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(1): 100-6, 2015 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-25616306

RESUMO

The defectiveness of bone marrow mesenchymal stem cells (BM-MSCs) in acquired aplastic anemia (AA) has been a frequent research topic in recent years. This review summarizes the defectiveness of BM-MSCs which is responsible for the mechanism of acquired AA and the prospective application of BM-MSCs in the treatment of acquired AA. An increasingly number of laboratory statistics has demonstrated that the defectiveness of BM-MSCs is more likely to play an important role in the pathogenesis of AA, namely, the apparently different biological characteristics and gene expression profiles, the decreased ability of supporting hematopoiesis as well as self-renewal and differentiation, and the exhaustion of regulating immune response of hematopoietic environment. Those abnormalities continuously prompt AA to become irreversible bone marrow failure along with the imbalanced immunity. With deepening research on MSCs, infusion of MSCs for the primary purpose of recovering hematopoietic microenvironment may become a new approach for the treatment of AA.


Assuntos
Anemia Aplástica/etiologia , Células-Tronco Mesenquimais/fisiologia , Anemia Aplástica/imunologia , Anemia Aplástica/terapia , Medula Óssea , Diferenciação Celular , Proliferação de Células , Citocinas/análise , Humanos , Ativação Linfocitária , Transplante de Células-Tronco Mesenquimais , Linfócitos T Reguladores/imunologia
16.
Exp Hematol ; 43(4): 309-18.e2, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25534202

RESUMO

Our recent study identified a nonsense mutation of La-related protein 4B (LARP4B) from whole genome sequencing of a 3-year-old female monozygotic twin pair discordant for MLL-associated acute myeloid leukemia (AML). To study the role of LARP4B in AML, we established a LARP4B-knockdown MLL-AF9 AML mouse model. Using this mouse model, we found that LARP4B knockdown significantly decreased leukemia cells in the peripheral blood, spleen, and bone marrow and prolonged the survival of AML recipient mice. Additional studies showed that LARP4B knockdown reduced leukemia stem cells (LSCs) and impaired the self-renew capacity of LSCs. Cell cycle analysis revealed that LARP4B knockdown arrested more LSCs in the G0 phase. The transcription of the cell cycle inhibitors p16, p19, and p21 and of the lineage-specific transcription factor CCAAT-enhancer-binding protein α was increased in the LARP4B-knockdown LSCs. Thus, our results demonstrate that LARP4B plays an important role in the maintenance of LSCs and suggest that LARP4B may regulate the cell cycle of LSCs via suppressing the expression of the cell cycle inhibitors p16, p19, and p21 and the myeloid specific transcription factor CCAAT-enhancer-binding protein α.


Assuntos
Autoantígenos/fisiologia , Ciclo Celular , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia , Ribonucleoproteínas/fisiologia , Animais , Autoantígenos/genética , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Humanos , Leucemia Mieloide Aguda/metabolismo , Camundongos , Ribonucleoproteínas/genética
17.
Pediatr Blood Cancer ; 61(12): 2256-62, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25176567

RESUMO

BACKGROUND: Primary myelofibrosis (PMF) is quite rare in children. Mutations of JAK2(V617F) or MPL(W515K/L) were absent in pediatric patients with PMF according to previous studies. Recently, mutations in calreticulin (CALR) were described in adult patients with JAK2/MPL-unmutated PMF. Our study aimed to analyze the clinical and genetic features of Chinese pediatric patients with PMF. PROCEDURES: We retrospectively investigated 14 pediatric patients diagnosed as PMF according to WHO 2008 criteria. Direct sequencing was performed for the existence of genetic alterations in JAK2, MPL, TET2, CBL, ASXL1, IDH1, IDH2, SRSF2, EZH2, DNMT3A and CALR. RESULTS: In our cohort, all patients had anemia, three patients (21%) had splenomegaly, six patients (43%) had micromegakaryocytes at time of diagnosis. No patient had spontaneous remission and six patients (43%) transformed to acute myelocytic leukemia. In nine patients with evaluable cytogenetic information, three subjects (33%) had abnormal karyotypes. The median survival from time of diagnosis was 28 months. Seven patients (50%) had type 2 mutations of CALR. No patient had mutations in the other candidate genes. There was no statistical differences in age, gender, hemoglobin, WBC, neutrophil and platelet counts, percentage of circulating blast, overall survival and leukemia transformation between patients with and without CALR mutation. CONCLUSION: Our study documented that Chinese pediatric patients with PMF in our cohort had its own clinical characteristics and poor outcome. CALR mutations were detected in 50% of our pediatric patients with PMF. Based on our study, CALR mutations screening could be used as molecular marker for diagnosis of pediatric patients with PMF.


Assuntos
Calreticulina/genética , Mutação/genética , Mielofibrose Primária/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Masculino , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
18.
Nan Fang Yi Ke Da Xue Xue Bao ; 26(3): 364-6, 2006 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-16546750

RESUMO

OBJECTIVE: To construct a three-dimensional model to demonstrate the relation between the anterior branches of lumbosacral 4,5, lumbosacral trunk, and the pelvis. METHODS: An formaldehyde-fixed adult cadaver was dissected to expose the anterior branches of the lumbar nerves 4 and 5, lumbosacral trunk and the sacroiliac. The mixture of titanium powder and adhesive was smeared on the surface of the major branches of L4 and L5 nerves, lumbosacral trunk, femoral nerves and obturator nerves. As soon as the mixture solidified, the specimen was scanned by spiral CT at 3 mm intervals to obtain 159 two-dimensional sectional images for three-dimensional model reconstruction on a personal computer using the software 3-D DOCTOR. RESULTS AND CONCLUSION: The reconstructed model can well demonstrate the spatial relation between the nerves and the pelvis, and allows rotation in every direction, which at the same time can be conveniently applied for purpose of clinical teaching.


Assuntos
Imagem Tridimensional , Plexo Lombossacral/diagnóstico por imagem , Articulação Sacroilíaca/diagnóstico por imagem , Nervos Espinhais/diagnóstico por imagem , Adulto , Cadáver , Humanos , Região Lombossacral/diagnóstico por imagem , Masculino , Ossos Pélvicos/diagnóstico por imagem , Pelve/diagnóstico por imagem , Radiografia
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