Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Neoplasias Primárias Múltiplas/genética , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Cariótipo Anormal , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bandeamento Cromossômico , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/ultraestrutura , Células Clonais/química , Células Clonais/patologia , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias Primárias Múltiplas/patologia , Células-Tronco Neoplásicas/química , Células-Tronco Neoplásicas/patologia , Reação em Cadeia da Polimerase em Tempo Real , Translocação GenéticaRESUMO
Partial monosomy 21 results in a great variability of clinical features that may be associated with the size and location of the deletion. In this study, we report a 22-month-old girl who showed a 45,XX,add(12)(p13)dn,-21 karyotype. The final cytogenomic result was 45,XX,der(12)t(12;21)(p13;q22.11) dn,-21.arr[hg19] 21q11.2q22.11(14824453_33868129)×1 revealing a deletion from 21pter to 21q22.11. Clinical manifestation of the patient included hypertonia, a long philtrum, epicanthic folds, low-set ears, and café-au-lait macules - a phenotype considered as mild despite the relatively large size of the deletion compared to patients from the literature.
Assuntos
Anormalidades Múltiplas/genética , Manchas Café com Leite/genética , Deleção Cromossômica , Cromossomos Humanos Par 21/ultraestrutura , Face/anormalidades , Hipertonia Muscular/genética , Cromossomos Humanos Par 21/genética , Deficiências do Desenvolvimento/genética , Feminino , Perda Auditiva Bilateral/genética , Humanos , Recém-Nascido , Cariotipagem , Fenótipo , Escoliose/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Leucemia Mieloide Aguda/induzido quimicamente , Segunda Neoplasia Primária/induzido quimicamente , Translocação Genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator de Ligação a CCAAT/genética , Inversão Cromossômica , Terapia Combinada , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Cadeias Pesadas de Miosina/genética , Segunda Neoplasia Primária/genética , Proteínas de Fusão Oncogênica/genética , Transplante de Células-Tronco de Sangue Periférico , Proteína 1 Parceira de Translocação de RUNX1/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transplante AutólogoAssuntos
Anemia Macrocítica/genética , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Janus Quinase 2/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Mutação de Sentido Incorreto , Neoplasias Primárias Múltiplas/tratamento farmacológico , Idoso , Biomarcadores Tumorais , Medula Óssea/patologia , Deleção Cromossômica , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 5/genética , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Indução de Remissão , Translocação GenéticaRESUMO
BACKGROUND: The optimal monitoring schedules and cutoff minimal residual disease (MRD) levels for the accurate prediction of relapse at all time points after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with t(8;21) acute myeloid leukemia (AML). METHODS: RUNX1-RUNX1T1 transcript levels were measured in bone marrow samples collected from 208 patients at scheduled time points after transplantation (1530 samples in total). RESULTS: A total of 92.3% of the requested samples were collected, and 74.0% of patients had complete sample collection. The 1-, 3-, and 6-month RUNX1-RUNX1T1 transcript levels could significantly discriminate between continuous complete remission and a hematologic relapse at 1.5-3, 4-6, and 7-12 months but not at >3, >6, and >12 months, respectively. Over 90% of the 175 patients who were in continuous complete remission had a ≥3-log reduction in RUNX1-RUNX1T1 transcript levels from the time of diagnosis at each time point after transplantation and a ≥4-log reduction at ≥12 months. A <3-log reduction within 12 months and/or a <4-log reduction at ≥12 months was significantly related to a higher 3-year cumulative incidence of relapse (CIR) rate in both the entire cohort and the patients with no intervention after HSCT (58.4 vs. 2.2%, 76.5 vs. 2.0%; all P < 0.0001). Patients who had received a preemptive donor lymphocyte infusion when the increase in RUNX1-RUNX1T1 transcripts was ≤1-log according to the above dual cutoff values had significantly lower 1-year CIR rate after intervention than the patients who had received an infusion when the increase was >1-log (0 vs. 55.0%, P = 0.015). CONCLUSIONS: RUNX1-RUNX1T1 transcripts with a <3-log reduction from diagnosis within 12 months and/or a <4-log reduction at ≥12 months after allo-HSCT could accurately predict relapse and may prompt a timely intervention in patients with t(8;21) AML.
Assuntos
Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Subunidade alfa 2 de Fator de Ligação ao Core/biossíntese , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/biossíntese , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Proteína 1 Parceira de Translocação de RUNX1/biossíntese , Translocação Genética , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Proteínas de Fusão Oncogênica/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Recidiva , Adulto JovemRESUMO
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 de Retinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Tretinoína/farmacologia , Células U937RESUMO
Epigenetic dysregulation is a hallmark of cancer executed by a number of complex processes the most important of which converge on DNA methylation and histone protein modifications. Epigenetic marks are potentially reversible and thus promising drug targets. In the setting of acute lymphoblastic leukemia (ALL) they have been associated with clinicopathological features including risk of relapse or molecular subgroups of the disease. Here, using immunocytochemistry of bone marrow smears from diagnosis, we studied global histone H4 acetylation, whose loss was previously linked to treatment failure in adults with ALL, in pediatric patients. We demonstrate that preserved global histone H4 acetylation is significantly associated with favorable outcome (RFS, EFS, OS) in children with B cell progenitor (BCP) ALL, recapitulating the findings from adult populations. Further, for the first time we demonstrate differential histone H4 acetylation in molecular subclasses of BCP-ALL including cases with ETV6-RUNX1 fusion gene or PAX5 deletion or deletions in genes linked to B cell development. We conclude global histone H4 acetylation is a prognostic marker and a potential therapeutic target in ALL.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Epigênese Genética , Histonas/metabolismo , Proteínas de Fusão Oncogênica/fisiologia , Fator de Transcrição PAX5/deficiência , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Acetilação , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Cromossomos Humanos Par 12/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Multiplex , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Processamento de Proteína Pós-Traducional , Indução de Remissão , Translocação Genética , Resultado do TratamentoRESUMO
Interphase heterogenous chromosomes spatially close to each other are predominantly located near the center of nuclei and are prone to incur translocations. We screened a t(8;21) (q22;q22) acute myeloid leukemia-M2 patient during three phases (post-chemotherapy, remittent stage, and relapse) and a donor of normal karyotype as control by two-(2D) and three-dimensional (3D)-fluorescence in situ hybridization (FISH). Our classification of nuclei (normal, transitional, and malignant nuclei) by 3D-FISH analyses may provide a more precise prognosis than 2D-FISH results, especially for remittent stage sample in our study, in which 2D-FISH findings showed normal results, whereas 3D-FISH results showed extreme abnormalities (normal nuclei 27%, transitional nuclei 36%, malignant nuclei 37%). The relative radial positions (d/R) of chromosomes 8 were similar to d/R of chromosomes 21 for the relapse sample. We classified heterogenous chromosome pairs into close pairs and normal pairs based on their relative distances (d'/(2R)). The centers of close pairs were more internal than normal pairs in nuclei in all samples, and the d/R values of a given-type pairwise heterogenous chromosomes were similar among four samples. Our data demonstrate that the classification of nuclei based on spatial organization of chromosomes by 3D-FISH is reasonable and essential for evaluating acute myeloid leukemia prognosis.
Assuntos
Núcleo Celular/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Imunofenotipagem/métodos , Hibridização in Situ Fluorescente/métodos , Interfase , Leucemia Mieloide Aguda/genética , Translocação Genética , Células da Medula Óssea/ultraestrutura , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , PrognósticoRESUMO
Core binding factor (CBF)-positive acute myeloid leukemia (AML) presents a favorable prognosis, except for patients with KIT mutation, especially D816 mutation. The current retrospective study attempted to validate a prognostic role of KIT mutation in 121 Korean patients with CBF AML. The study patients consisted of 121 patients with CBF AML (82 patients with RUNX1/RUNX1T1 [67.8 %] and 39 patients with CBFB/MYH11 [32.2 %]) recruited from eight institutions in Korea. All patients received idarubicin plus cytarabine or behenoyl cytosine arabinoside 3 + 7 induction chemotherapy. The KIT gene mutation status was determined by direct sequencing analyses. A KIT mutation was detected in 32 cases (26.4 %) in our series of patients. The KIT mutation was most frequent in exon 17 (n = 18, 14.9 %; n = 16 with D816 mutation), followed by exon 8 (n = 10, 8.3 %). The presence of KIT D816 mutation was associated with adverse outcomes for the event-free survival (p = 0.03) and for the overall survival (p = 0.02). The unfavorable impact of D816 mutation was more prominent when the analysis was confined to the RUNX1/RUNX1T1 subtype. The KIT mutation was detected in 26.4 % of Korean patients with CBF AML. The KIT D816 mutation demonstrated an unfavorable prognostic implication, particularly in the RUNX1/RUNX1T1 subtype.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Idoso , Inversão Cromossômica , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/ultraestrutura , Terapia Combinada , Fatores de Ligação ao Core/análise , Fatores de Ligação ao Core/genética , Citarabina/administração & dosagem , Citarabina/análogos & derivados , Intervalo Livre de Doença , Éxons/genética , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Idarubicina/administração & dosagem , Estimativa de Kaplan-Meier , Coreia (Geográfico)/epidemiologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/cirurgia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/análise , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1 , Translocação Genética , Resultado do Tratamento , Adulto JovemRESUMO
The translocation t(1;19)(q23;p13)/der(19)t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19)t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1·8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7 years, the median white blood cell (WBC) count was 16 × 10(9)/l, and the female/male ratio was 1·2. The predicted event-free survival (EFS) at 5 and 10 years was 0·79, whereas the predicted overall survival (OS) at 5 and 10 years was 0·85 and 0·82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19)t(1;19) (P = 0·004).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomos Humanos Par 19/genética , Cromossomos Humanos Par 1/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Translocação Genética , Adolescente , Aneuploidia , Criança , Pré-Escolar , Cromossomos Humanos Par 1/ultraestrutura , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 12/ultraestrutura , Cromossomos Humanos Par 19/ultraestrutura , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/ultraestrutura , Intervalo Livre de Doença , Finlândia/epidemiologia , Seguimentos , Humanos , Islândia/epidemiologia , Lactente , Estimativa de Kaplan-Meier , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Recidiva , Países Escandinavos e Nórdicos/epidemiologia , Resultado do TratamentoRESUMO
Therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myelogenous leukemia (t-AML) in patients with acute promyelocytic leukemia (APL) are rare events. The cumulative exposure to chemotherapy with alkylating agents and topoisomerase II inhibitors is associated with t-AML that may develop any time after the completion of the treatment. We report the case of an acquired AML who previously received therapy for APL, after two years of being diagnosed. The diagnosis was established by morphologic findings, membrane markers, cytogenetic studies, and fluorescence in situ hybridization (FISH). To our knowledge this is the first documented case in Puerto Rico of a patient with APL that developed a t-AML without the characteristic chromosomal and morphologic findings of APL.
Assuntos
Leucemia Mieloide Aguda/etiologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Segunda Neoplasia Primária/etiologia , Translocação Genética , Adulto , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromossomos Humanos Par 15/ultraestrutura , Cromossomos Humanos Par 17/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 3/ultraestrutura , Cromossomos Humanos Par 7 , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Sinergismo Farmacológico , Evolução Fatal , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Promielocítica Aguda/genética , Masculino , Mercaptopurina/administração & dosagem , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Monossomia , Segunda Neoplasia Primária/genética , Tretinoína/administração & dosagemRESUMO
Recently it has been suggested that the human brain contains aneuploid cells; however the nature and magnitude of neural aneuploidy in health and disease remain obscure. Here, we have monitored aneuploidy in the cerebral cortex of the normal, Alzheimer's disease (AD) and ataxia telangiectasia (AT) brain by molecular cytogenetic approaches scoring more than 480,000 neural cells. Using arbitrarily selected set of DNA probes for chromosomes 1, 7, 11, 13, 14, 17, 18, 21, X and Y we have determined the mean rate of stochastic aneuploidy per chromosome as 0.5% in the normal human brain (95%CI 0.2-0.7%; SD 0.2%). The overall proportion of aneuploid cells in the normal brain has been estimated at approximately 10%. In the AT brain, we observed a 2-to-5 fold increase of stochastic aneuploidy randomly affecting different chromosomes (mean 2.1%; 95%CI - 1.5-2.6%; SD 0.8%). The overall proportion of aneuploid cells in the brain of AT individuals was estimated at approximately 20-50%. Compared with sex- and age-matched controls, the level of stochastic aneuploidy in the AD brain was not significantly increased. However, a dramatic 10-fold increase of chromosome 21-specific aneuploidy (both hypoploidy and hyperploidy) was detected in the AD cerebral cortex (6-15% versus 0.8-1.8% in control). We conclude that somatic mosaic aneuploidy differentially contributes to intercellular genomic variation in the normal, AD and AT brain. Neural aneuploidy leading to altered cellular physiology may significantly contribute to the pathogenesis of neurodegenerative diseases. These data indicate neural aneuploidy to be a newly identified feature of neurodegenerative diseases, similar to other devastative disorders hallmarked by aneuploidy such as chromosome syndromes and cancer.
Assuntos
Doença de Alzheimer/patologia , Aneuploidia , Ataxia Telangiectasia/patologia , Córtex Cerebral/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Núcleo Celular/genética , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Criança , Aberrações Cromossômicas/estatística & dados numéricos , Mapeamento Cromossômico/métodos , Cromossomos/genética , Cromossomos/metabolismo , Cromossomos/ultraestrutura , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/metabolismo , Cromossomos Humanos Par 21/ultraestrutura , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mosaicismo/estatística & dados numéricos , Neurônios/metabolismo , Neurônios/patologia , Adulto JovemRESUMO
Drooling generally arises as a result of neurologic or muscular impairments, especially in subjects affected by cerebral palsies. It has never previously been described in patients with ring chromosome 21 syndrome. We describe the video-assisted surgical rehabilitation of the left parotid duct in a child with ring chromosome 21 syndrome and a persistent and painful swelling of the left parotid region after the surgical ligation of the Stensen ducts because of drooling. The diagnosis of Stensen duct dilatation as a result of iatrogenous complete distal acquired atresia was made by means of clinical and magnetic resonance evaluations. Video-assisted sialoendoscopical surgical rehabilitation of the left parotid duct was successfully performed; based on this experience, this minimally invasive procedure is preferred before traditional invasive parotid surgery in these cases. Other therapeutical options such as botulinum toxin therapy might be considered for the management of drooling in such young patients.
Assuntos
Transtornos Cromossômicos/complicações , Cromossomos Humanos Par 21/ultraestrutura , Endoscopia/métodos , Ligadura/efeitos adversos , Cromossomos em Anel , Ductos Salivares/cirurgia , Doenças das Glândulas Salivares/reabilitação , Sialorreia/cirurgia , Cirurgia Vídeoassistida/métodos , Adolescente , Dilatação Patológica/etiologia , Dilatação Patológica/cirurgia , Humanos , Doença Iatrogênica , Masculino , Ductos Salivares/patologia , Doenças das Glândulas Salivares/etiologia , Doenças das Glândulas Salivares/cirurgia , Salivação , Sialorreia/etiologia , StentsRESUMO
We present a case of acute myeloblastic leukemia (AML-M2) with a complex t(8;21) translocation and additional acquired chromosomes yielding a hyperdiploid karyotype. AML1/ETO transcript was observed by reverse transcription-polymerase chain reaction. Fluorescence in situ hybridization (FISH), spectral karyotyping (SKY), and comparative genomic hybridization (CGH) were performed to further identify the chromosomes observed by G banding. The patient was treated according to our current protocol for AML. He remains in complete remission +11 months from diagnosis. Further follow-up of this patient and the analysis of a larger number of children are needed to define whether the gains of the specific extra chromosomes modify the good prognosis that t(8;21) confers to this subgroup of AML.
Assuntos
Aneuploidia , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusão Oncogênica/genética , Translocação Genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Citarabina/administração & dosagem , Análise Citogenética , Etoposídeo/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase , Proteína 1 Parceira de Translocação de RUNX1RESUMO
Ollier disease is a rare disorder characterized by the presence of multiple enchondromas and a propensity to develop malignancies. We report the case of a 7-year-old Caucasian male with Ollier disease who developed acute myelogenous leukemia (AML). This report describes a patient with Ollier disease and AML and may offer a clue into the genetic pathogenesis of these disorders.
Assuntos
Encondromatose/genética , Leucemia Mieloide Aguda/etiologia , Síndromes Neoplásicas Hereditárias/genética , Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Cromossomos Humanos Par 14/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Gemtuzumab , Doença Enxerto-Hospedeiro , Humanos , Lactente , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/cirurgia , Masculino , Mitoxantrona/administração & dosagem , Translocação GenéticaRESUMO
The t(8;21)(q22;q22) occurs frequently in acute myelogenous leukaemia and gives rise to the transcription factor fusion protein, RUNX1-RUNX1T1 (also known as AML1-ETO). To identify the genes dysregulated by the aberrant transcriptional activity of RUNX1-RUNX1T1, we used microarrays to determine the effect of this mutation on gene expression in human progenitor cells and during subsequent development. Gene signatures of these developmental subsets were very dissimilar indicating that effects of RUNX1-RUNX1T1 are highly context dependent. We focused on gene changes associated with the granulocytic lineage and identified a clinically relevant subset of these by comparison with 235 leukaemia patient transcriptional signatures. We confirmed the overexpression of a number of significant genes (Sox4, IL-17BR, CD200 and gamma-catenin). Further, we show that overexpression of CD200 and gamma-catenin is also associated with the inv(16) abnormality which like RUNX1-RUNX1T1 disrupts core binding factor activity. We investigated the functional significance of CD200 and gamma-catenin overexpression in normal human progenitor cells. The effect of IL17 on growth was also assessed. Individually, none of these changes were sufficient to recapitulate the effects of RUNX1-RUNX1T1 on normal development. These data provide the most comprehensive and pertinent assessment of the effect of RUNX1-RUNX1T1 on gene expression and demonstrate the highly context-dependent effects of this fusion gene.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Regulação Leucêmica da Expressão Gênica/genética , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide Aguda/genética , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/fisiologia , Transcrição Gênica/genética , Antígenos CD/biossíntese , Antígenos CD/genética , Linhagem Celular Tumoral/metabolismo , Linhagem da Célula , Células Cultivadas/metabolismo , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/ultraestrutura , Desmoplaquinas/genética , Desmoplaquinas/fisiologia , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/patologia , Proteínas de Grupo de Alta Mobilidade/biossíntese , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Leucemia Mieloide Aguda/patologia , Proteínas de Neoplasias/biossíntese , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , Proteína 1 Parceira de Translocação de RUNX1 , Receptores de Interleucina-17/biossíntese , Receptores de Interleucina-17/genética , Proteínas Recombinantes de Fusão/fisiologia , Fatores de Transcrição SOXC , Transativadores/biossíntese , Transativadores/genética , Translocação Genética , gama Catenina/genética , gama Catenina/fisiologiaRESUMO
Histone deacetylase inhibitor valproic acid (VPA) was recently shown to enhance proliferation and self-renewal of normal hematopoietic stem cells, raising the possibility that VPA may also support growth of leukemic progenitor cells (LPC). Here, VPA maintains a significantly higher proportion of CD34+ LPC and colony forming units compared to control cultures in six AML samples, but selectively reduces leukemic cell numbers in another AML sample with expression of AML1/ETO. Our data suggest a differential effect of VPA on the small population of AML progenitor cells and the bulk of aberrantly differentiated blasts in the majority of AML samples tested.
Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Inibidores de Histona Desacetilases , Leucemia Mieloide/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Ácido Valproico/efeitos adversos , Adulto , Idoso , Antígenos CD34/análise , Técnicas de Cultura de Células/métodos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral/citologia , Linhagem Celular Tumoral/efeitos dos fármacos , Cromossomos Humanos Par 21/ultraestrutura , Cromossomos Humanos Par 8/ultraestrutura , Subunidade alfa 2 de Fator de Ligação ao Core/análise , Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Feminino , Células-Tronco Hematopoéticas/citologia , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide/enzimologia , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/citologia , Proteínas de Fusão Oncogênica/análise , Proteínas de Fusão Oncogênica/fisiologia , Proteína 1 Parceira de Translocação de RUNX1 , Translocação Genética , Ensaio Tumoral de Célula-Tronco , Ácido Valproico/farmacologiaRESUMO
BACKGROUND: Human myelogenous leukemia characterized by either the non random t(8; 21)(q22; q22) or t(16; 21)(q24; q22) chromosome translocations differ for both their biological and clinical features. Some of these features could be consequent to differential epigenetic transcriptional deregulation at AML1 targets imposed by AML1-MTG8 and AML1-MTG16, the fusion proteins deriving from the two translocations. Preliminary findings showing that these fusion proteins lead to transcriptional downregulation of AML1 targets, marked by repressive chromatin changes, would support this hypothesis. Here we show that combining conventional global gene expression arrays with the power of bioinformatic genomic survey of AML1-consensus sequences is an effective strategy to identify AML1 targets whose transcription is epigenetically downregulated by the leukemia-associated AML1-MTG16 protein. RESULTS: We interrogated mouse gene expression microarrays with probes generated either from 32D cells infected with a retroviral vector carrying AML1-MTG16 and unable of granulocyte differentiation and proliferation in response to the granulocyte colony stimulating factor (G-CSF), or from 32D cells infected with the cognate empty vector. From the analysis of differential gene expression alone (using as criteria a p value < 0.01 and an absolute fold change > 3), we were unable to conclude which of the 37 genes downregulated by AML1-MTG16 were, or not, direct AML1 targets. However, when we applied a bioinformatic approach to search for AML1-consensus sequences in the 10 Kb around the gene transcription start sites, we closed on 17 potential direct AML1 targets. By focusing on the most significantly downregulated genes, we found that both the AML1-consensus and the transcription start site chromatin regions were significantly marked by aberrant repressive histone tail changes. Further, the promoter of one of these genes, containing a CpG island, was aberrantly methylated. CONCLUSION: This study shows that a leukemia-associated fusion protein can impose a distinct epigenetic repressive signature at specific sites in the genome. These findings strengthen the conclusion that leukemia-specific oncoproteins can induce non-random epigenetic changes.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Epigênese Genética/genética , Regulação Leucêmica da Expressão Gênica/genética , Inativação Gênica , Leucemia Mieloide/genética , Proteínas de Neoplasias/genética , Proteínas Repressoras/fisiologia , Animais , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Cromatina/genética , Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 16/ultraestrutura , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 21/ultraestrutura , Sequência Consenso , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Ilhas de CpG , Regulação para Baixo/genética , Perfilação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/farmacologia , Histonas/metabolismo , Humanos , Interleucina-3/farmacologia , Leucemia Mieloide/metabolismo , Camundongos , Células Mieloides/efeitos dos fármacos , Células Mieloides/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/fisiologia , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteínas Recombinantes de Fusão/fisiologia , Proteínas Repressoras/genética , Sítio de Iniciação de Transcrição , Transfecção , Translocação GenéticaRESUMO
Ligands specifically binding to leukemia cells may be used for drug targeting, resulting in more effective treatment with less side effects. Little is known about receptors specifically expressed on acute myeloid leukemia (AML) cells or ligands thereof. We selected random phage display peptide libraries on Kasumi-1 AML cells. A peptide with the sequence CPLDIDFYC was enriched. Phage displaying this peptide strongly bound to Kasumi-1 and SKNO-1 cells and binding could be inhibited by the cognate peptide. Both, Kasumi-1 and SKNO-1 cells carry the chromosomal translocation t(8;21), leading to aberrant expression of the fusion protein AML1/ETO. CPLDIDFYC also strongly and specifically bound primary AML1/ETO-positive AML blasts as well as U-937 cells with forced AML1/ETO expression, suggesting that the CPLDIDFYC receptor may be upregulated upon AML1/ETO expression. Gene expression profiling comparing a panel of CPLDIDFYC-binding and CPLDIDFYC-nonbinding cell lines identified a set of potential receptors for the CPLDIDFYC peptide. Further analysis suggested that alpha4beta1 integrin (VLA-4) is the CPLDIDFYC receptor. Finally, we showed that the CPLDIDFYC-phage is internalized upon receptor binding, suggesting that the CPLDIDFYC-receptor-ligand interaction may be exploitable for targeting drugs or gene therapy vectors to leukemia cells carrying the suitable receptor.
