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3.
Anticancer Res ; 39(8): 4329-4332, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366525

RESUMO

BACKGROUND/AIM: Acute myeloid leukemia is well characterized by chromosomal aberrations that correspond to various subtypes of acute leukemias. The t(8;21)(q22;q22) is a frequent chromosomal abnormality strongly associated with acute myeloblastic leukemia with maturation (AML-M2), but is rarely associated with other subtypes. Translocation involving a third chromosome could produce new genetic rearrangements that lead to leukemogenesis. PATIENTS AND METHODS: Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) were performed to identify the karyotype. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the AML1/ETO transcript. RESULTS/CONCLUSION: We herein report a novel rearrangement with a three-way translocation involving chromosomes 8, 21 and another unknown chromosome, in an 83-year-old female patient diagnosed as AML-M4, with an ALM1/ETO negative transcript. This is an uncommon case of AML-M4 with three-way translocation in a new variant of t(8;21) acute myeloid leukaemia. The detailed mechanism of different phenotype expression is unclear. Further study is needed to identify the leukemogenetic transformation resulting from t(8;21) translocation.


Assuntos
Análise Citogenética , Cariótipo , Leucemia Mielomonocítica Aguda/genética , Translocação Genética/genética , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Cariotipagem/métodos , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/patologia
4.
Br J Haematol ; 180(6): 919-924, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29441563

RESUMO

Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3. This proposed diagnostic group is supported by (i) retained myeloid differentiation potential during early T cell lymphoid development, (ii) recognition that some cases of acute myeloid leukaemia (AML) harbour hallmarks of T cell development, such as T-cell receptor gene rearrangements and (iii) common gene mutations in subsets of AML and T cell acute lymphoblastic leukaemia (T-ALL), including WT1, PHF6, RUNX1 and BCL11B. This proposed diagnostic entity overlaps with early T cell precursor (ETP) T-ALL and T cell/myeloid mixed phenotype acute leukaemias (MPALs), and also includes a subset of leukaemias currently classified as AML with features of T-lymphoblastic development. The proposed classification of AMTL as a distinct entity would enable more precise prospective diagnosis and permit the development of improved therapies for patients whose treatment is inadequate with current approaches.


Assuntos
Leucemia Mielomonocítica Aguda , Leucemia de Células T , Humanos , Leucemia Mielomonocítica Aguda/classificação , Leucemia Mielomonocítica Aguda/diagnóstico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/terapia , Leucemia de Células T/classificação , Leucemia de Células T/diagnóstico , Leucemia de Células T/genética , Leucemia de Células T/terapia , Células Mieloides , Proteínas de Neoplasias/genética , Células Precursoras de Linfócitos T
6.
Artif Cells Nanomed Biotechnol ; 46(8): 1792-1798, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29113504

RESUMO

Acute myeloid leukaemia (AML) is a genetically heterogeneous, severe and rapidly progressing disease triggered by blocking granulocyte or monocyte differentiation and maturation. Overexpression of myeloid cell leukaemia-1 (Mcl-1) and Survivin is associated with drug resistance, tumour progression and inhibition of apoptotic mechanisms in leukaemia and several cancers. In the present study, we examined the combined effect of etoposide and dual siRNA-mediated silencing of Mcl-1 and Survivin on U-937 AML cells. The AML cells were co-transfected with Mcl-1 and Survivin-specific siRNAs and genes silencing were confirmed by quantitative real-time PCR and Western blotting. Subsequently, MTT assay was used for the evaluation of cytotoxic effects by dual siRNA and etoposide on their own and in combination. For the studying of apoptosis, DNA-histone ELISA and annexin-V/FITC assays were performed. Co-transfection of Mcl-1 and Survivin siRNA significantly blocked their expression at the mRNA and protein levels, leading to the induction of apoptosis and strong inhibition of growth (p < .05). Besides, combined treatment of etoposide with Mcl-1 and Survivin siRNAs co-transfection leads to synergistically enhance etoposide-induced cytotoxic and apoptotic effects (p < .05). The results showed that Mcl-1 and Survivin play a major role in the U937 cells survival and their resistance relative to etoposide. Thus, Mcl-1 and Survivin can be considered as promising molecular targets for the treatment of AML. The combination treatment with etoposide, and siRNA-mediated silencing of corresponding genes may be a novel strategy in chemoresistance AML treatment.


Assuntos
Apoptose , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/farmacologia , Inativação Gênica , Leucemia Mielomonocítica Aguda/terapia , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Survivina/antagonistas & inibidores , Humanos , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , RNA Interferente Pequeno/genética , Survivina/biossíntese , Survivina/genética , Células U937
8.
Eur J Hum Genet ; 25(8): 1020-1024, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28513614

RESUMO

Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.


Assuntos
Códon sem Sentido , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Janus Quinase 2/genética , Leucemia Mielomonocítica Aguda/genética , Proteínas/genética , Adulto , Criança , Feminino , Mutação em Linhagem Germinativa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucemia Mielomonocítica Aguda/diagnóstico , Masculino , Linhagem , Transdução de Sinais
10.
Int J Cancer ; 140(5): 1159-1172, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27859216

RESUMO

PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11G503A . To study the impact of PTPN11G503A cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11wt , the cells harboring PTPN11G503A were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11G503A autonomously differentiated into macrophages (1.8%) in the medium containing IL3. Further studies showed that the cells had an elevated (∼2.9-fold) Csf1 transcription level and secreted more (∼4.5-fold) M-CSF to the medium which can stimulate monocyte/macrophage differentiation of BM cells. Mice transplanted with the cells harboring PTPN11G503A had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11wt , the cells harboring PTPN11G503A had an increased competitive engraftment and clonal expansion in the BM and spleen of recipient mice, although no competitive growth advantage was observed in the in vitro co-culturing assays. The mice transplanted with the MLL/AF10(OM-LZ) cells harboring PTPN11wt developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11G503A -induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11G503A to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression.


Assuntos
Transformação Celular Neoplásica/genética , Leucemia Monocítica Aguda/etiologia , Leucemia Mielomonocítica Aguda/etiologia , Mutação de Sentido Incorreto , Proteína de Leucina Linfoide-Mieloide/fisiologia , Proteínas de Fusão Oncogênica/fisiologia , Mutação Puntual , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Animais , Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Técnicas de Cocultura , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Ativação Enzimática/genética , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Lactente , Interleucina-3/farmacologia , Leucemia Monocítica Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Fator Estimulador de Colônias de Macrófagos/sangue , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína de Leucina Linfoide-Mieloide/genética , Proteínas de Fusão Oncogênica/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/fisiologia , Quimera por Radiação , Transdução Genética , Células Tumorais Cultivadas/transplante
12.
Tumour Biol ; 37(8): 10107-14, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26820131

RESUMO

Recently, somatic mutations in SRSF2 gene have been discovered in a proportion of hematologic malignancies including acute myeloid leukemia (AML). This study was aimed to investigate SRSF2 mutations in Chinese AML patients. High-resolution melting analysis (HRMA) was developed to screen SRSF2 mutations in 249 cases with AML, and then direct DNA sequencing was used to verify the results of HRMA. In this study, 3.6 % (9/249) of Chinese AML patients were found with heterozygous SRSF2 mutations. Patients with SRSF2 mutations were older than those with wild-type SRSF2 (P = 0.014). No differences in the sex, blood parameters, French-American-British classification (FAB) subtypes, and karyotypes were observed between AML patients with and without SRSF2 mutations. Although the overall survival (OS) of SRSF2-mutated patients was inferior to those without mutations in both whole AML patients (median 4 vs. 11 months, respectively; P = 0.006) and cytogenetically normal patients (median 2 vs. 12 months, respectively; P = 0.008), multiple analysis disclosed that SRSF2 mutation was not an independent prognostic factor in AML patients. These results suggest that SRSF2 mutation occurs at a low frequency in aged AML patients and might not be associated with adverse prognosis in Chinese AML patients.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Leucemia Mieloide Aguda/genética , Mutação , Proteínas de Neoplasias/genética , Fatores de Processamento de Serina-Arginina/genética , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Heterozigoto , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/etnologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mielomonocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Método Simples-Cego , Adulto Jovem
13.
Cytogenet Genome Res ; 150(3-4): 281-286, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28253492

RESUMO

In pediatric acute myeloid leukemia (AML), chromosomal abnormalities leading to a disruption of the lysine methyltransferase 2A (KMT2A) gene in 11q23 are the most frequent rearrangements. Here, we report on the identification of a novel cryptic insertion, ins(11;X)(q23;q28q12), resulting in a translocation of the KMT2A gene in 11q23, leading to a KMT2A-FLNA fusion in a 13-month-old boy with de novo acute myelomonocytic leukemia, who died 38 days after diagnosis. The patient presented a complex karyotype 48∼49,Y,del(X)(q12),+del(X)(q12),+8,ins(11;X)(q23; q28q12),+19. The identified fusion gene was predicted to be out-of-frame (fusion of portions of KMT2A exon 11 with FLNA exon 11). However, RT-PCR experiments demonstrated that a potentially functional transcript was generated by alternative splicing where KMT2A exon 10 was spliced in-frame to the truncated FLNA exon 11. This case report helps to better understand the rare but potentially severe impact of KMT2A- FLNA fusions in infants with AML to improve prognostic stratification of therapy and clinical management.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Filaminas/genética , Fusão Gênica , Histona-Lisina N-Metiltransferase/genética , Leucemia Mielomonocítica Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Humanos , Lactente , Cariotipagem , Masculino
15.
Oncogene ; 35(15): 1965-76, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-26148230

RESUMO

The ETS transcription factor ERG has been implicated as a major regulator of both normal and aberrant hematopoiesis. In acute myeloid leukemias harboring t(16;21), ERG function is deregulated due to a fusion with FUS/TLS resulting in the expression of a FUS-ERG oncofusion protein. How this oncofusion protein deregulates the normal ERG transcription program is unclear. Here, we show that FUS-ERG acts in the context of a heptad of proteins (ERG, FLI1, GATA2, LYL1, LMO2, RUNX1 and TAL1) central to proper expression of genes involved in maintaining a stem cell hematopoietic phenotype. Moreover, in t(16;21) FUS-ERG co-occupies genomic regions bound by the nuclear receptor heterodimer RXR:RARA inhibiting target gene expression and interfering with hematopoietic differentiation. All-trans retinoic acid treatment of t(16;21) cells as well as FUS-ERG knockdown alleviate the myeloid-differentiation block. Together, the results suggest that FUS-ERG acts as a transcriptional repressor of the retinoic acid signaling pathway.


Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Regulação Neoplásica da Expressão Gênica/genética , Hematopoese/fisiologia , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Proteínas de Neoplasias/fisiologia , Proteínas de Fusão Oncogênica/fisiologia , Proteína FUS de Ligação a RNA/fisiologia , Transdução de Sinais/fisiologia , Translocação Genética , Tretinoína/fisiologia , Motivos de Aminoácidos , Linhagem Celular Tumoral , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Dimerização , Elementos Facilitadores Genéticos , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/fisiopatologia , Leucemia Mielomonocítica Aguda/patologia , Leucemia Mielomonocítica Aguda/fisiopatologia , Complexos Multiproteicos , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Proteínas de Fusão Oncogênica/genética , Regiões Promotoras Genéticas , Ligação Proteica , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , Proteína FUS de Ligação a RNA/antagonistas & inibidores , Proteína FUS de Ligação a RNA/genética , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Receptores X Retinoide/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia , Células U937
17.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 46(3): 403-8, 2015 May.
Artigo em Chinês | MEDLINE | ID: mdl-26121862

RESUMO

OBJECTIVE: To determine the impacts of Wnt signaling pathway products-polymorphisms of rs4135385, rs11079571 and rs7832767 located in ß-catenin gene (CTNNB1), Axin gene (AXIN2), and secreted frizzled-related protein gene (SFRP1) on the risk and treatment outcomes of acute leukemia. METHODS: Bone marrows (volume 1-1. 5 mL) were collected from 372 untreated patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), and peripheral blood samples (2. 0 mL) were obtained from 401 healthy controls for the purpose of total DNA extraction. Polymorphisms of rs4135385, rs11079571 and rs7832767 located in CTNNB1, AXIN2 and SFRP1 were genotyped with high-resolution melting method (HRM). Chi-square analyses were performed to compare the genotype and allele distributions of the three single nucleotides (SNPs) between the leukemia patients and healthy controls. Single factor variance tests were performed to compare the differences in clinical features among different genotype groups. Complete remission (CR) rates after induction chemotherapy were also compared between different genotype groups using Chi-square tests. RESULTS: No significant differences were found beiween the leukemia patients and healthy controls in the frequencies of alleles and genotypes of CTNNB1 rs4135385, SFRP1 rs7832767 polymorphisms. Those with A allele in AXIN2 rs11079571 polymorphism was less likely to have acute myelomonocytic/monocytic leukemia than those with G allele (P = 0. 016, OR=0. 677, 95%CI:0. 439-0. 930). Acute bead monocyte/mononuclear cell leukemia (AML-M4/5)patients with AA genotype presented higher platelet count (P = 0. 040), and higher complete remission rate after chemotherapy (P = 0. 040), compared with the patients with AG and GG genotypes. CONCLUSION: AML-M4/5 patients have less frequency of A allele in AXIN2 rs11079571 polymorphism than healthy controls. Patients carrying A allele have higher platelet counts and higher sensitivity to chemotherapy.


Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Aguda/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Via de Sinalização Wnt/genética , Alelos , Proteína Axina/genética , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Indução de Remissão , beta Catenina/genética
18.
Sci Rep ; 5: 8283, 2015 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-25655563

RESUMO

We present a system-wide transcriptional network structure that controls cell types in the context of expression pattern transitions that correspond to cell type transitions. Co-expression based analyses uncovered a system-wide, ladder-like transcription factor cluster structure composed of nearly 1,600 transcription factors in a human transcriptional network. Computer simulations based on a transcriptional regulatory model deduced from the system-wide, ladder-like transcription factor cluster structure reproduced expression pattern transitions when human THP-1 myelomonocytic leukaemia cells cease proliferation and differentiate under phorbol myristate acetate stimulation. The behaviour of MYC, a reprogramming Yamanaka factor that was suggested to be essential for induced pluripotent stem cells during dedifferentiation, could be interpreted based on the transcriptional regulation predicted by the system-wide, ladder-like transcription factor cluster structure. This study introduces a novel system-wide structure to transcriptional networks that provides new insights into network topology.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação Leucêmica da Expressão Gênica , Redes Reguladoras de Genes , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/patologia , Modelos Biológicos , Ésteres de Forbol/farmacologia , Transcrição Genética , Linhagem Celular Tumoral , Análise por Conglomerados , Biologia Computacional/métodos , Humanos
19.
Med Clin (Barc) ; 144(11): 487-90, 2015 Jun 08.
Artigo em Espanhol | MEDLINE | ID: mdl-24854193

RESUMO

BACKGROUND AND OBJECTIVE: Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) display similar clinical and hematological characteristics. The objective of the present study was to determine the mutational status of SETBP1 and CSF3R in these diseases. PATIENTS AND METHOD: The mutational status of SETBP1 and CSF3R was studied in 7 patients with aCML (n = 3), CNL (n = 1) and unclassifiable myeloproliferative neoplasms (MPN-u) (n = 3). Additionally, mutations in ASXL1, SRSF2, IDH1/2, DNMT3A, and RUNX1 were also analyzed. RESULTS: SETBP1 mutations (G870S and G872R) were detected in 2 patients with MPN-u, and one of them also presented mutations in SRSF2 (P95H) and ASXL1 (E635fs). The CNL case showed mutations in CSFR3 (T618I), SETBP1 (G870S) and SRSF2 (P95H). No patient classified as aCML had mutations in SETBP1 or CSF3R. One of the patients with mutations evolved to acute myeloid leukemia, while the other 2 had disease progression without transformation to overt leukemia. CONCLUSION: The knowledge of the molecular alterations involved in these rare diseases is useful in the diagnosis and may have an impact on both prognosis and therapy.


Assuntos
Proteínas de Transporte/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Neutrofílica Crônica/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Receptores de Fator Estimulador de Colônias/genética , Idoso , Idoso de 80 Anos ou mais , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Análise Mutacional de DNA , DNA de Neoplasias/genética , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Leucemia Mielomonocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Prognóstico , Proteínas Repressoras/genética , Ribonucleoproteínas/genética , Fatores de Processamento de Serina-Arginina
20.
Ann Hematol ; 94(2): 211-21, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25241285

RESUMO

Recently, mutations of the GATA binding protein 2 (GATA2) gene were identified in acute myeloid leukemia (AML) patients with CEBPA double mutations (CEBPA (double-mut)), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, 14 different missense GATA2 mutations, which were all clustered in the highly conserved N-terminal zinc finger 1 domain, were identified in 27.4, 6.7, and 1 % of patients with CEBPA (double-mut), CEBPA (single-mut), and CEBPA wild type, respectively. All but one patient with GATA2 mutation had concurrent CEBPA mutation. GATA2 mutations were closely associated with younger age, FAB M1 subtype, intermediate-risk cytogenetics, expression of HLA-DR, CD7, CD15, or CD34 on leukemic cells, and CEBPA mutation, but negatively associated with FAB M4 subtype, favorable-risk cytogenetics, and NPM1 mutation. Patients with GATA2 mutation had significantly better overall survival and relapse-free survival than those without GATA2 mutation. Sequential analysis showed that the original GATA2 mutations might be lost during disease progression in GATA2-mutated patients, while novel GATA2 mutations might be acquired at relapse in GATA2-wild patients. In conclusion, AML patients with GATA2 mutations had distinct clinic-biological features and a favorable prognosis. GATA2 mutations might be lost or acquired at disease progression, implying that it was a second hit in the leukemogenesis of AML, especially those with CEBPA mutation.


Assuntos
Fator de Transcrição GATA2/genética , Leucemia Mieloide/genética , Mutação , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Aberrações Cromossômicas , Progressão da Doença , Seguimentos , Genótipo , Humanos , Estimativa de Kaplan-Meier , Cariótipo , Leucemia Eritroblástica Aguda/tratamento farmacológico , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patologia , Leucemia Monocítica Aguda/tratamento farmacológico , Leucemia Monocítica Aguda/genética , Leucemia Monocítica Aguda/patologia , Leucemia Mieloide/tratamento farmacológico , Leucemia Mieloide/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mielomonocítica Aguda/tratamento farmacológico , Leucemia Mielomonocítica Aguda/genética , Leucemia Mielomonocítica Aguda/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Adulto Jovem
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