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1.
Leukemia ; 2017 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-28757616

RESUMO

Leukemia accepted article preview online, 31 July 2017. doi:10.1038/leu.2017.237.

2.
Cell Death Differ ; 22(7): 1144-57, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25501596

RESUMO

Erythropoiesis is a tightly regulated process in which multipotential hematopoietic stem cells produce mature red blood cells. Here we show that deletion of poly(ADP-ribose) polymerase-2 (PARP-2) in mice leads to chronic anemia at steady state, despite increased erythropoietin plasma levels, a phenomenon not observed in mice lacking PARP-1. Loss of PARP-2 causes shortened lifespan of erythrocytes and impaired differentiation of erythroid progenitors. In erythroblasts, PARP-2 deficiency triggers replicative stress, as indicated by the presence of micronuclei, the accumulation of γ-H2AX (phospho-histone H2AX) in S-phase cells and constitutive CHK1 and replication protein A phosphorylation. Transcriptome analyses revealed the activation of the p53-dependent DNA-damage response pathways in PARP-2-deficient cells, culminating in the upregulation of cell-cycle and cell death regulators, concomitant with G2/M arrest and apoptosis. Strikingly, while loss of the proapoptotic p53 target gene Puma restored hematocrit levels in the PARP-2-deficient mice, loss of the cell-cycle regulator and CDK inhibitor p21 leads to perinatal death by exacerbating impaired fetal liver erythropoiesis in PARP-2-deficient embryos. Although the anemia displayed by PARP-2-deficient mice is compatible with life, mice die rapidly when exposed to stress-induced enhanced hemolysis. Our results pinpoint an essential role for PARP-2 in erythropoiesis by limiting replicative stress that becomes essential in the absence of p21 and in the context of enhanced hemolysis, highlighting the potential effect that might arise from the design and use of PARP inhibitors that specifically inactivate PARP proteins.


Assuntos
Replicação do DNA , Células Precursoras Eritroides/metabolismo , Eritropoese/fisiologia , Poli(ADP-Ribose) Polimerases/genética , Estresse Fisiológico/genética , Animais , Apoptose , Eritropoese/genética , Pontos de Checagem da Fase G2 do Ciclo Celular , Deleção de Genes , Histonas/metabolismo , Camundongos
5.
Leukemia ; 25(1): 110-20, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20882045

RESUMO

This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients' characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (P<0.001 for both outcomes), platelet count (P<0.001 and P=0.001, respectively) and proportion of bone marrow blasts (P<0.001 and P=0.016, respectively). The number of chromosomal abnormalities defined three risk categories for AML transformation (del(5q), del(5q)+1 and del(5q)+ ≥ 2 abnormalities) and two for OS (one group: del(5q) and del(5q)+1; and del(5q)+ ≥ 2 abnormalities, as the other one); with a median survival time of 58.0 and 6.8 months, respectively. Platelet count (P=0.001) and age (P=0.034) predicted OS in patients with '5q-syndrome'. This study demonstrates the importance of additional chromosomal abnormalities in MDS patients with deletion 5q, challenges the current '5q-syndrome' definition and constitutes a useful reference series to properly analyze the results of clinical trials in these patients.


Assuntos
Aberrações Cromossômicas , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Macrocítica/genética , Anemia Macrocítica/mortalidade , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Estudos Retrospectivos
6.
Leuk Res ; 35(2): 163-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20542566

RESUMO

NPM mutations are the most common genetic abnormalities found in non-promyelocytic AML. NPM-positive patients usually show a normal karyotype, a peculiar morphologic appearance with frequent monocytic traits and good prognosis in the absence of an associated FLT3 mutation. This report describes the immunophenotypic and genetic characteristics of a consecutive series of NPM-mutated de novo AML patients enroled in the CETLAM trial. Eighty-three patients were included in the study. Complete immunophenotype was obtained using multiparametric flow cytometry. Associated genetic lesions (FLT3, MLL, CEBPA and WT1 mutations) were studied by standardized methods. Real-time PCR was employed to assess the minimal residual status. The most common pattern was CD34-CD15+ and HLA-DR+. Small CD34 populations with immunophenotypic aberrations (CD15 and CD19 coexpression, abnormal SSC) were detected even in CD34 negative samples. Nearly all cases expressed CD33 (strong positivity), CD13 and CD117, and all were CD123+. The stem cell marker CD110 was also positive in most cases. Biologic parameters such as a high percentage of intermediate CD45+ (blast gate) (>75% nucleated cells), CD123+ and FLT3-ITD mutations were associated with a poor outcome. Quantitative PCR positivity had no prognostic impact either after induction or at the end of chemotherapy. Only PCR positivity (greater than 10 copies) detected in patients in haematological remission was associated with an increased relapse rate. Further studies are required to determine whether the degree of leukemic stem cell expansion (CD45+CD123+cells) increases the risk of acquisition of FLT3-ITD and/or provides selective advantages.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Proteínas Nucleares/genética , Adulto , Idoso , Antígenos CD/biossíntese , Proteínas Estimuladoras de Ligação a CCAAT/genética , Feminino , Citometria de Fluxo , Genes do Tumor de Wilms , Histona-Lisina N-Metiltransferase , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , Nucleofosmina , Prognóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética
7.
Int J Hematol ; 88(4): 387-395, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18820995

RESUMO

The World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues (2001) defined a provisional entity named refractory anemia with ringed sideroblasts associated to marked thrombocytosis (RARS-MT). Diagnosis of RARS-MT requires more than 15% of ringed sideroblasts in bone marrow aspirate and the existence of a thrombocytosis in blood, with a platelet count above 600 x 10(9)/L. Nevertheless, controversy exists regarding this platelet count "cut-off" value and, when RARS-MT was defined, the JAK2 mutation and its importance in the study of myeloproliferative disorders was unknown. We present the results of a Spanish retrospective multicentric study, which includes 76 cases of RARS with associated thrombocytosis (platelet count above 400 x 10(9)/L) at diagnosis (RARS-T), 36 of them with a platelet count above 600 x 10(9)/L. Our aim was to analyze their clinical, analytical and morphological characteristics, and to establish correlations with the JAK2 mutational status.


Assuntos
Anemia Refratária/genética , Anemia Refratária/patologia , Janus Quinase 2/genética , Mutação de Sentido Incorreto , Trombocitose/genética , Trombocitose/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Anemia Refratária/sangue , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Feminino , Humanos , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Estudos Retrospectivos , Trombocitose/sangue
8.
Leukemia ; 22(7): 1368-76, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18480837

RESUMO

To explore the gene expression signature in essential thrombocythemia (ET) patients in relation to JAK2V617F mutational status, expression profiling in circulating granulocytes was performed. Twenty ET were studied by microarray analysis and the results were confirmed by real-time quantitative RT-PCR in 40 ET patients, not receiving cytoreductive treatment. A heterogeneous molecular signature characterized by two main gene expression patterns was found: one with an upregulation of inflammatory genes related to neutrophil activation and thrombosis, and the other with significantly lower expression of these genes. Supervised clustering analysis showed 30 genes differentially expressed between JAK2V617F-negative and JAK2V617F-positive ET patients. Among the JAK2V617F-negative, a set of 14 genes (CISH, C13orf18, CCL3, PIM1, MAFF, SOCS3, ID2, GADD45B, KLF5, TNF, LAMB3, HRH4, TAGAP and TRIB1) showed an abnormal expression pattern. In this group of patients, CISH, SOCS2, SOCS3 and PIM1 genes, all involved in JAK-STAT signalling pathway, presented a lower expression. A two-gene predictor model was built comprising FOSB and CISH genes, which were the best discriminators of JAK2V617F status. In conclusion, JAK2V617F-negative ET patients present a characteristic gene expression profile, different from JAK2V617F-positive patients. Other pathways, besides JAK-STAT, might be implicated in the pathophysiology of JAK2V617F-negative ET patients.


Assuntos
Perfilação da Expressão Gênica , Janus Quinase 2/genética , Mutação , Trombocitemia Essencial/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais
9.
Br J Dermatol ; 158(5): 1129-33, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18294313

RESUMO

Myeloid or type 1 dendritic cell leukaemia is an exceedingly rare haematopoietic neoplasm characterized by a specific immunophenotypic profile close to plasmacytoid dendritic cell and acute myelogenous leukaemia. A 77-year-old man presenting specific cutaneous infiltration by myeloid dendritic cell leukaemia is reported. The clinical features as well as the cutaneous histopathological and immunohistochemical features led to the initial diagnosis of CD4+/CD56+ haematodermic neoplasm. However, extensive immunophenotypic studies performed from peripheral blood blasts disclosed that leukaemic cells expressed myeloid dendritic cell markers, confirming the diagnosis. The diagnostic difficulties of specific cutaneous involvement by myeloid dendritic cell leukaemia on the basis of routine histopathological and immunohistochemical features are highlighted.


Assuntos
Antígenos CD4/análise , Antígeno CD56/análise , Células Dendríticas/imunologia , Leucemia Mieloide Aguda/imunologia , Neoplasias Cutâneas/imunologia , Idoso , Evolução Fatal , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/patologia , Masculino , Neoplasias Cutâneas/patologia
13.
Leukemia ; 20(1): 87-94, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16281071

RESUMO

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.


Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Leucemia Mieloide/genética , Neoplasia Residual/genética , Doença Aguda , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Inversão Cromossômica , Análise Citogenética , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Cinética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Neoplasia Residual/terapia , Prognóstico , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Taxa de Sobrevida
14.
Br J Dermatol ; 153(4): 838-41, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16181472

RESUMO

Neutral lipid storage disease (Chanarin-Dorfman syndrome) is an autosomal recessive metabolic disorder associated with congenital ichthyosis and a multisystemic accumulation of neutral lipids (lipid droplets) in various types of cells. The clinical presentation has been reported to correspond to that of nonbullous congenital ichthyosiform erythroderma. We report a 4-year-old boy presenting a generalized ichthyosiform disorder manifested by migrating scaly plaques alternating with areas of normal-looking skin, showing erythematous borders with sharp margins, clinically suggestive of erythrokeratoderma variabilis (EKV). A peripheral blood smear revealed cytoplasmic vacuoles in most granulocytes. Genetic studies from the patient and his parents revealed that the patient carried two different and novel mutations of the ABHD5 gene: a nonsense mutation in exon 6 (transmitted by the father) and an insertion/deletion in exon 4 (transmitted by the mother). Our observation demonstrates the clinical heterogeneity of the ichthyosiform dermatoses observed in Chanarin-Dorfman syndrome and widens the clinical range of conditions presenting migrating scaly plaques mimicking EKV.


Assuntos
Eritrodermia Ictiosiforme Congênita/patologia , Erros Inatos do Metabolismo Lipídico/patologia , 1-Acilglicerol-3-Fosfato O-Aciltransferase , Pré-Escolar , Esterases/genética , Humanos , Eritrodermia Ictiosiforme Congênita/genética , Lipase/genética , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Mutação , Síndrome , Vacúolos/patologia
15.
Leuk Res ; 29(10): 1109-16, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16095690

RESUMO

BACKGROUND AND OBJECTIVES: A consecutive series of acute myeloid leukemias (AML) patients was analyzed in conditions which reduce the inter-assay variations (the same flow cytometer, the same observers and the same panel of monoclonal antibodies) in order to investigate the prognostic information provided by flow cytometry. DESIGN AND METHODS: Two hundred and sixty-six bone marrow (BM) samples from 326 patients enrolled in the LMA-99 protocol from the CETLAM group were studied by multiparametric flow cytometry. Immunophenotyping studies were performed on erythrocyte-lysed BM samples. Antigen expression of leukemic cells was analyzed using triple stainings with fluorochrome-conjugated combinations of monoclonal antibodies. RESULTS: CD2 was positive in 21 cases (8%); an associated inv(16) was detected in eight CD2+ cases (38%). Two-year overall survival (OS) rate for CD2+/inv(16)+ patients was 75%, whereas it was 0% for CD2+/inv(16)- patients and 47% for CD2- patients (p=0.0001). CD36 was expressed in 37% of patients (n=98). Two-year leukemia-free survival (LFS) rate was 34% for CD36+ patients and 55% for CD36- patients (p=0.001). In the multivariate analysis, CD2+ (RR=8.4; p=0.0001) and adverse karyotype (RR=10.2; p=0.0001) were associated with a lower CR rate, CD36+ (RR=1.5; p=0.03), CD2+ (RR=2; p=0.04) and adverse karyotype (RR=4; p=0.0001) were associated with a lower OS and CD36+ (RR=2; p=0.002) and adverse karyotype (RR=3.5; p=0.005) predicted a lower LFS. CONCLUSIONS: CD2+ patients had a very poor OS when CD2/inv(16)+ cases were excluded. CD36 and CD2 expression at diagnosis can provide prognostically important information in adult de novo AML.


Assuntos
Antígenos CD2/metabolismo , Antígenos CD36/metabolismo , Leucemia Mieloide/metabolismo , Doença Aguda , Adolescente , Adulto , Anticorpos Monoclonais , Medula Óssea/metabolismo , Medula Óssea/patologia , Aberrações Cromossômicas , Inversão Cromossômica , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Cariotipagem , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
16.
Bone ; 34(2): 330-5, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14962811

RESUMO

Idiopathic myelofibrosis (IMF) induces dramatic changes in bone. Bone remodeling and densitometric alterations in a series of nine patients with IMF and their relationship with the histologic stage of the disease were assessed. Patients were included at diagnosis and a bone marrow biopsy, dual-energy X-ray absorptiometry, and transiliac bone biopsy for histomorphometric analysis were performed. Five cases were classified as IMF histologic stage 1, one as stage 2, and three as stage 3. Compared with 40 age- and sex-matched controls, the following histomorphometric parameters were significantly higher in our patients: bone volume (BV/TV), osteoblast surface (Ob.S/BS), eroded surface (ES/BS), osteoclast surface (Oc.S/BS), osteoclast number (N.Oc/TA), mineralizing surface (MS/BS), reversal period (Rv.P), and remodeling period (Rm.P). Mineral apposition rate (MAR) and erosion depth (E.Depth) were significantly decreased (P < 0.05 for all comparisons). Bone mineral density (BMD) measurements showed high values for patient age and sex both at femur neck (Z score range +0.19 to +7) and total femur (Z score range -0.09 to +6.48). When densitometric values were analyzed according to IMF histologic stage, patients in stages 1 and 2 had significantly lower BMD values than to those in stage 3 (P = 0.024). In conclusion, patients with IMF present a characteristic bone histomorphometric pattern with increased bone volume and bone cells but low apposition and decreased erosion depth, suggesting a positive balance in bone remodeling units. This balance would produce the increase in bone mass observed in this disease. Given the increase in BMD observed with more advanced stages of IMF, this noninvasive method could be useful tool for assessing IMF progression.


Assuntos
Remodelação Óssea/fisiologia , Osso e Ossos/anatomia & histologia , Osso e Ossos/fisiologia , Mielofibrose Primária/patologia , Mielofibrose Primária/fisiopatologia , Fenômenos Biomecânicos , Densidade Óssea/fisiologia , Densitometria , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
17.
Eur J Haematol ; 71(3): 211-4, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12930323

RESUMO

Here, we report the case of a child who, since birth, showed persistent macrocytosis and elevated mean corpuscular volume of the erythrocytes. Bone marrow biopsy revealed gross disorganisation of the erythroblastic series both at the light and electron microscopic examination, with complete absence of dysplastic features in the granulocytic and megakaryocytic series. Common causes of macrocytosis were excluded. The spectrum of morphological findings were not consistent with any of the classical types of congenital dyserythropoietic anaemias (CDAs) and serological findings of CDA type II were absent. The most outstanding feature was a marked irregularity of the nuclear outline of the late erythroblasts that presented thick-ending finger-like projections. The combination of macrocytosis without anaemia and these morphologic erythroblastic changes have not been previously reported in the setting of classical and variant forms of CDAs.


Assuntos
Anemia Diseritropoética Congênita/patologia , Eritroblastos/patologia , Anemia Diseritropoética Congênita/sangue , Biópsia , Medula Óssea/patologia , Índices de Eritrócitos , Humanos , Lactente , Fígado/patologia , Masculino , Microscopia Eletrônica
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