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1.
Genes (Basel) ; 14(11)2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-38003028

RESUMO

The patient reported here underwent hematopoietic stem cell transplantation (HSCT) due to chronic granulomatous disease (CGD) caused by biallelic mutations of the NCF1 gene. Two years later, he developed AML, which was unexpected and was recognized via sex-mismatched chromosomes as deriving from the donor cells; the patient was male, and the donor was his sister. Donor cell leukemia (DCL) is very rare, and it had never been reported in patients with CGD after HSCT. In the subsequent ten years, the AML relapsed three times and the patient underwent chemotherapy and three further HSCTs; donors were the same sister from the first HSCT, an unrelated donor, and his mother. The patient died during the third relapse. The DCL was characterized since onset by an acquired translocation between chromosomes 9 and 11, with a molecular rearrangement between the MLL and MLLT3 genes-a quite frequent cause of AML. In all of the relapses, the malignant clone had XX sex chromosomes and this rearrangement, thus indicating that it was always the original clone derived from the transplanted sister's cells. It exhibited the ability to remain quiescent in the BM during repeated chemotherapy courses, remission periods and HSCT. The leukemic clone then acquired different additional anomalies during the ten years of follow-up, with cytogenetic results characterized both by anomalies frequent in AML and by different, non-recurrent changes. This type of cytogenetic course is uncommon in AML.


Assuntos
Doença Granulomatosa Crônica , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Masculino , Doença Granulomatosa Crônica/genética , Doença Granulomatosa Crônica/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doadores não Relacionados , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patologia , Translocação Genética
2.
Blood ; 138(7): 557-570, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34010415

RESUMO

Bone marrow (BM) microenvironment contributes to the regulation of normal hematopoiesis through a finely tuned balance of self-renewal and differentiation processes, cell-cell interaction, and secretion of cytokines that during leukemogenesis are altered and favor tumor cell growth. In pediatric acute myeloid leukemia (AML), chemotherapy is the standard of care, but >30% of patients still relapse. The need to accelerate the evaluation of innovative medicines prompted us to investigate the role of mesenchymal stromal cells (MSCs) in the leukemic niche to define its contribution to the mechanism of leukemia drug escape. We generated a humanized 3-dimensional (3D) niche with AML cells and MSCs derived from either patients (AML-MSCs) or healthy donors. We observed that AML cells establish physical connections with MSCs, mediating a reprogrammed transcriptome inducing aberrant cell proliferation and differentiation and severely compromising their immunomodulatory capability. We confirmed that AML cells modulate h-MSCs transcriptional profile promoting functions similar to the AML-MSCs when cocultured in vitro, thus facilitating leukemia progression. Conversely, MSCs derived from BM of patients at time of disease remission showed recovered healthy features at transcriptional and functional levels, including the secretome. We proved that AML blasts alter MSCs activities in the BM niche, favoring disease development and progression. We discovered that a novel AML-MSC selective CaV1.2 channel blocker drug, lercanidipine, is able to impair leukemia progression in 3D both in vitro and when implanted in vivo if used in combination with chemotherapy, supporting the hypothesis that synergistic effects can be obtained by dual targeting approaches.


Assuntos
Proliferação de Células , Leucemia Mieloide Aguda/metabolismo , Células-Tronco Mesenquimais/metabolismo , Transcriptoma , Canais de Cálcio Tipo L/metabolismo , Di-Hidropiridinas/farmacologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Células-Tronco Mesenquimais/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral
5.
Oncotarget ; 8(66): 109915-109923, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29299118

RESUMO

L-Asparaginase (L-Asp) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid, and its depletion induces leukemic cell death. L-Asp is an important component of treatment regimens for Acute Lymphoblastic Leukemia (ALL). Sensitivity to L-Asp is due to the absence of L-Asparagine synthetase (ASNS), the enzyme that catalyzes the biosynthesis of L-asparagine. ASNS gene is located on 7q21.3, and its increased expression in ALLs correlates with L-Asp resistance. Chromosome 7 monosomy (-7) is a recurrent aberration in myeloid disorders, particularly in adverse-risk Acute Myeloid Leukemias (AMLs) and therapy-related myeloid neoplasms (t-MN), that leads to a significant downregulation of the deleted genes, including ASNS. Therefore, we hypothesized that -7 could affect L-Asp sensitivity in AMLs. By treating AML cell lines and primary cells from pediatric patients with L-Asp, we showed that -7 cells were more sensitive than AML cells without -7. Importantly, both ASNS gene and protein expression were significantly lower in -7 AML cell lines, suggesting that haploinsufficiency of ASNS might induce sensitivity to L-Asp in AMLs. To prove the role of ASNS haploinsufficiency in sensitizing AML cells to L-Asp treatment, we performed siRNA-knockdown of ASNS in AML cell lines lacking -7, and observed that ASNS knockdown significantly increased L-Asp cytotoxicity. In conclusion, -7 AMLs showed high sensitivity to L-Asp treatment due to low expression of ASNS. Thus, L-Asp may be considered for treatment of AML pediatric patients carrying -7, in order to improve the outcome of adverse-risk AMLs and t-MN patients.

7.
Blood ; 124(24): 3577-82, 2014 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-25270907

RESUMO

MYC translocations represent a genetic subtype of T-lineage acute lymphoblastic leukemia (T-ALL), which occurs at an incidence of ∼6%, assessed within a cohort of 196 T-ALL patients (64 adults and 132 children). The translocations were of 2 types; those rearranged with the T-cell receptor loci and those with other partners. MYC translocations were significantly associated with the TAL/LMO subtype of T-ALL (P = .018) and trisomies 6 (P < .001) and 7 (P < .001). Within the TAL/LMO subtype, gene expression profiling identified 148 differentially expressed genes between patients with and without MYC translocations; specifically, 77 were upregulated and 71 downregulated in those with MYC translocations. The poor prognostic marker, CD44, was among the upregulated genes. MYC translocations occurred as secondary abnormalities, present in subclones in one-half of the cases. Longitudinal studies indicated an association with induction failure and relapse.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Translocação Genética , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 6/metabolismo , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 7/metabolismo , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Taxa de Sobrevida , Trissomia/genética
8.
Int J Hematol ; 99(2): 208-12, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24338706

RESUMO

A twin pair affected by juvenile myelomonocytic leukemia (JMML) with the same somatic PTPN11 mutation and abnormal chromosome 7 in bone marrow samples but distinct prognostic gene expression signatures, received a matched-unrelated donor and matched-unrelated cord blood transplant, respectively. Both twins fully engrafted, but after 6 months, the twin with an acute-myeloid-like (AML-like) signature at diagnosis rejected the graft and had an autologous reconstitution. A second transplant with an unrelated 5/6-HLA-matched-loci cord blood performed after 4 months from rejection was unsuccessful. After 25 months from diagnosis, the twin with the AML-like gene expression signature died of liver failure while on progression of his JMML. The other twin, who had a non-acute-myeloid-like (non-AML-like) gene expression signature at diagnosis is in complete hematological remission with full donor chimera. This observation suggests a biological diversity of JMML also in patients with a common genetic background.


Assuntos
Doenças em Gêmeos/terapia , Rejeição de Enxerto/fisiopatologia , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mielomonocítica Juvenil/terapia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/imunologia , Doenças em Gêmeos/metabolismo , Evolução Fatal , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Rejeição de Enxerto/imunologia , Humanos , Lactente , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/imunologia , Leucemia Mielomonocítica Juvenil/metabolismo , Masculino , Prognóstico , Indução de Remissão , Transplante Homólogo , Resultado do Tratamento , Gêmeos Monozigóticos
9.
Leuk Res ; 37(8): 928-35, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23735857

RESUMO

Multiple lesions in genes that are involved in cell cycle control, proliferation, survival and differentiation underlie T-cell acute lymphoblastic leukaemia (T-ALL). We translated these biological insights into clinical practice to improve diagnostic work-ups and patient management. Combined interphase fluorescence in situ hybridization (CI-FISH), single nucleotide polymorphism (SNP), and gene expression profiles (GEP) were applied in 51 children with T-ALL who were stratified according to minimal residual disease (MRD) risk categories (AIEOP-BFM ALL2000). CI-FISH identified type A abnormalities in 90% of patients. Distribution of each was in line with the estimated incidence in childhood T-ALL: 37.5% TAL/LMO, 22.5% HOXA, 20% TLX3, 7.5% TLX1, and 2.5% NKX2-1. GEP predictions concurred. SNP detected type B abnormalities in all cases, thus linking type A and B lesions. This approach provided an accurate, comprehensive genomic diagnosis and a complementary GEP-based classification of T-ALL in children. Dissecting primary and secondary lesions within MRD categories could improve prognostic criteria for the majority of patients and be a step towards personalized diagnosis.


Assuntos
Genômica/métodos , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Predisposição Genética para Doença/genética , Genótipo , Humanos , Hibridização in Situ Fluorescente/métodos , Cariótipo , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
12.
Blood ; 117(26): 7102-11, 2011 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-21551233

RESUMO

We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 11 , Rearranjo Gênico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 8 , Estudos de Coortes , Análise Citogenética , Feminino , Estudos de Associação Genética , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Translocação Genética , Trissomia
13.
Pediatr Blood Cancer ; 55(3): 446-51, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20658615

RESUMO

BACKGROUND: Anaplastic large cell lymphoma (ALCL) constitutes approximately 15% of pediatric and 3% of adult non-Hodgkin lymphomas. Most pediatric cases harbor the reciprocal translocation t(2;5)(p23;q35), involving the alk gene. Cytogenetic studies of ALCL have mostly been published as case-reports. The aim of this study was to determine the cytogenetic profiles of a series of pediatric ALCL and to compare them with pediatric and adult ALCL from the literature. METHODS: Eighteen children treated at our Institution were studied by standard cytogenetic analysis and RT-PCR for the specific t(2;5) translocation product. Comparative analysis was performed on our findings and on the karyotypes of 48 pediatric and 39 adult ALCL reported in the literature. RESULTS: Karyotype was obtained in 16/18 ALCL: 9 showed translocation t(2;5) and 1 an alk variant form. Structural and numeric chromosomal abnormalities were identified in both pediatric and adult series. Trisomies were found preferentially in pediatric patients (P = 0.013) and monosomies in adults (P = 0.038). Trisomy 7 was found in 22% (13/59) of pediatric cases with abnormal karyotype and only in 5% (2/38) of adults; monosomy of chromosome 13 in 13% (5/38) of adults and only in 2% (1/59) of pediatric patients and monosomy of chromosome 15 in 16% (6/38) of adults and in none of the pediatric ALCL. CONCLUSION: Our data suggest that pediatric and adult ALCL are characterized by different numerical chromosomal abnormalities. Larger prospective studies may elucidate their potential prognostic impact.


Assuntos
Linfoma Anaplásico de Células Grandes/genética , Adolescente , Adulto , Quinase do Linfoma Anaplásico , Criança , Aberrações Cromossômicas , Diploide , Feminino , Humanos , Masculino , Monossomia , Proteínas Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética , Trissomia
14.
Blood ; 114(12): 2489-96, 2009 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-19528532

RESUMO

Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.


Assuntos
Cromossomos Humanos Par 11/genética , Rearranjo Gênico , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Translocação Genética , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 9/genética , Intervalo Livre de Doença , Histona-Lisina N-Metiltransferase , Humanos , Hibridização in Situ Fluorescente , Agências Internacionais , Cariotipagem , Prognóstico , Estudos Retrospectivos
15.
Cancer Chemother Pharmacol ; 64(6): 1235-51, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19363609

RESUMO

PURPOSE: Pyrrolotetrazinones are a new class of azolotetrazinones endowed with a high, remarkable antiproliferative activity in human tumor cultured cells. They hold the deaza skeleton of the antitumor drug temozolomide, although preliminary investigations indicated a different mechanism of action. To understand their mechanism(s) of action along with their target at molecular level, four derivatives were selected on the basis of their activity on a panel of human tumor cell lines and they were investigated in depth in a T leukemia cell line (Jurkat). METHODS AND RESULTS: Flow cytometric analysis of cell cycle after treatment with pyrrolotetrazinones has demonstrated that they were able to induce an arrest of the cell cycle in G2/M phase. This effect was accompanied by apoptosis of the treated cells which is further characterized by exposure of phosphatidylserine on the external surface of the cell membranes. Mitochondria were strongly involved in the apoptotic pathway as demonstrated by the induced mitochondrial depolarization, generation of reactive oxygen species, and activation of caspase-3. Western blot analysis showed that Bcl-2 expression was down regulated whereas the proapototic protein Bax was upregulated in a time dependent manner. Moreover, these compounds induced a clear increase in the mitotic index, and inhibited microtubule assembly in vitro indicating that pyrrolotetrazinones, at variance with temozolomide, involved an efficacious inhibition of tubulin polymerization in their mechanism of action. Interestingly compound 3 at the concentration of 50 mg/kg body weight significantly inhibited in vivo the growth of a syngeneic hepatocellular carcinoma in Balb/c mice. CONCLUSION: These results suggest that pyrrolotetrazinones inhibit microtubule polymerization, induce G2/M arrest of cell cycle and cause apoptosis through the mitochondrial pathway identifying them as novel effective antimitotic agents with potential for clinical development.


Assuntos
Apoptose/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Caspase 3/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dacarbazina/química , Dacarbazina/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Células Jurkat , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Microtúbulos/química , Microtúbulos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fosfatidilserinas/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Temozolomida , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapêutico , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
16.
Genes Chromosomes Cancer ; 48(1): 22-38, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18803328

RESUMO

Pediatric acute lymphoblastic leukemia (ALL) comprises genetically distinct subtypes. However, 25% of cases still lack defined genetic hallmarks. To identify genomic aberrancies in childhood ALL patients nonclassifiable by conventional methods, we performed a single nucleotide polymorphisms (SNP) array-based genomic analysis of leukemic cells from 29 cases. The vast majority of cases analyzed (19/24, 79%) showed genomic abnormalities; at least one of them affected either genes involved in cell cycle regulation or in B-cell development. The most relevant abnormalities were CDKN2A/9p21 deletions (7/24, 29%), ETV6 (TEL)/12p13 deletions (3/24, 12%), and intrachromosomal amplifications of chromosome 21 (iAMP21) (3/24, 12%). To identify variation in expression of genes directly or indirectly affected by recurrent genomic alterations, we integrated genomic and gene expression data generated by microarray analyses of the same samples. SMAD1 emerged as a down-regulated gene in CDKN2A homozygous deleted cases compared with nondeleted. The JAG1 gene, encoding the Jagged 1 ligand of the Notch receptor, was among a list of differentially expressed (up-regulated) genes in ETV6-deleted cases. Our findings demonstrate that integration of genomic analysis and gene expression profiling can identify genetic lesions undetected by routine methods and potential novel pathways involved in B-progenitor ALL pathogenesis.


Assuntos
Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Cromossomos Humanos Par 21/genética , Feminino , Deleção de Genes , Regulação Leucêmica da Expressão Gênica , Genes p16 , Marcadores Genéticos , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-1 , Masculino , Proteínas de Membrana/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fator de Transcrição PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Repressoras/genética , Proteínas Serrate-Jagged , Proteína Smad1/genética , Dissomia Uniparental , Variante 6 da Proteína do Fator de Translocação ETS
17.
Pediatr Blood Cancer ; 52(3): 357-63, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19061215

RESUMO

BACKGROUND: The diagnosis of myelodysplastic syndromes (MDS) is mainly based on morphology and cytogenetic analysis. Several efforts to analyze MDS by flow cytometry have been reported in adults. These studies have focused on the identification of abnormalities in the maturation pathway of antigen expression of myelo-monocytic cells, and characterization of blast populations. Therefore, phenotype has been proposed as a diagnostic and prognostic criterion tool for adult MDS. The current article provides data concerning the blast phenotype in pediatric MDS. PROCEDURE: We evaluated by multiparameter flow cytometry 26 MDS pediatric patients with more than 2% of blast cells at bone marrow morphological examination (17 de novo MDS and 9 secondary MDS) and 145 pediatric de novo acute myeloid leukemia (AML) cases (M3 excluded). As control group, 12 healthy age-matched donors for allogenic bone marrow transplantation (BMD) and 6 regenerating bone marrow samples, collected from children with acute lymphoblastic leukemia (ALL) in remission after induction chemotherapy, were studied. RESULTS: We identified a blast immunophenotype typically expressed in most MDS cases and a strong correlation between CD7 expression and poor outcome. CD34+ compartment in MDS bone marrow was also analyzed: a significant decrease of B-cell precursors was detected in MDS patients independent of age. CONCLUSIONS: Our data suggest that the blasts phenotypic features can constitute a diagnostic and prognostic tool also for pediatric MDS.


Assuntos
Crise Blástica/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Adolescente , Antígenos CD34/análise , Antígenos CD34/imunologia , Antígenos CD7/análise , Antígenos CD7/imunologia , Crise Blástica/metabolismo , Crise Blástica/patologia , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Humanos , Imunofenotipagem , Masculino , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/patologia , Estadiamento de Neoplasias , Células Precursoras de Linfócitos B/citologia , Células Precursoras de Linfócitos B/imunologia , Prognóstico , Taxa de Sobrevida
18.
Mol Cancer ; 7: 80, 2008 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-18947387

RESUMO

Chromosomal translocations play a crucial role in tumorigenesis, often resulting in the formation of chimeric genes or in gene deregulation through position effects. T-cell acute lymphoblastic leukemia (T-ALL) is associated with a large number of such rearrangements. We report the ectopic expression of the 3' portion of EST DA926692 in the bone marrow of a childhood T-ALL case showing a t(2;11)(q11.2;p15.1) translocation as the sole chromosome abnormality. The breakpoints, defined at the sequence level, mapped within HPS5 (Hermansky Pudlak syndrome 5) intron 1 at 11p15.1, and DA926692 exon 2 at 2q11.2. The translocation was accompanied by a submicroscopic inversion that brought the two genes into the same transcriptional orientation. No chimeric trancript was detected. Interestingly, Real-Time Quantitative (RQ)-PCR detected, in the patient's bone marrow, expression of a 173 bp product corresponding to the 3' portion of DA926692. Samples from four T-ALL cases with a normal karyotype and normal bone marrow used as controls were negative. It might be speculated that the juxtaposition of this genomic segment to the CpG island located upstream HPS5 activated DA92669 expression. RQ-PCR analysis showed expression positivity in 6 of 23 human tissues examined. Bioinformatic analysis excluded that this small non-coding RNA is a precursor of micro-RNA, although it is conceivable that it has a different, yet unknown, functional role. To the best of our knowledge, this is the first report, in cancer, of the activation of a small non-coding RNA as a result of a chromosomal translocation.


Assuntos
Medula Óssea/metabolismo , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 2/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , RNA não Traduzido/genética , Translocação Genética , Adolescente , Sequência de Bases , Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Masculino , Dados de Sequência Molecular , RNA não Traduzido/metabolismo
19.
Am J Surg Pathol ; 31(3): 454-9, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17325488

RESUMO

We report 2 intra-abdominal tumors originally diagnosed as leiomyosarcomas, occurring in adolescents, one as a second malignancy after a Hodgkin lymphoma. Both tumors exhibited unusual morphologic features characterized by spindle cells arranged in sheets or in fascicles, devoid of the typical desmoplastic stroma. Cytokeratins and mesenchymal markers, including smooth muscle actin, desmin, and muscle specific actin, were coexpressed in the tumor cells, whereas EMA was negative. Reverse transcription-polymerase chain reaction analysis showed an EWS-WT1 fusion transcript. Both patients are alive and in complete remission at 3 and 13 years after diagnosis, respectively. These tumors raise a variety of diagnostic possibilities. They could represent intra-abdominal desmoplastic small round cell tumor, with histologic features of epithelioid leiomyosarcoma or an unusual subtype of leiomyosarcoma with an EWS-WT1 transcript. Alternatively, they could represent an unrecognized subgroup of tumors with spindle cell morphology, bearing the same translocation as desmoplastic small round cell tumor, but characterized by a more favorable clinical course.


Assuntos
Neoplasias Abdominais/patologia , Carcinoma de Células Pequenas/secundário , Leiomiossarcoma/patologia , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Abdominais/genética , Neoplasias Abdominais/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/metabolismo , Criança , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 22 , Análise Citogenética , Desmina/metabolismo , Intervalo Livre de Doença , Humanos , Leiomiossarcoma/genética , Leiomiossarcoma/metabolismo , Masculino , Segunda Neoplasia Primária , Proteínas de Fusão Oncogênica/genética , RNA Neoplásico/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação Genética
20.
Genes Chromosomes Cancer ; 40(3): 165-71, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15138996

RESUMO

Familial platelet disorder with propensity to acute myelogenous leukemia, or FPD/AML (OMIM #601399), is a rare autosomal dominant condition, with only 12 families reported. It is characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies. Causal mutations have been identified in the RUNX1 gene (also known as AML1, CBFA2) in the 11 families so far analyzed. RUNX1 is a gene frequently involved in the pathogenesis of sporadic leukemia and myelodysplastic syndromes, through acquired chromosome rearrangements and point mutations. We report an Italian family with three members affected with FPD/AML, two sibs and their father, who developed myelodysplastic syndromes (which in one subsequently evolved into AML). Direct sequencing and polymorphisms haplotype analysis of the region of chromosome 21 where RUNX1 is mapped demonstrated that FPD/AML in this family was not caused by any mutation of the RUNX1 gene, thus providing evidence for the genetic heterogeneity of this disorder. Cytogenetic studies showed monosomy 7 in the marrow of all the three affected subjects, as well as an independent clone with trisomy 8 in the father. The importance of mutator effects in the pathogenesis of familial myeloid malignancies characterized by relevant chromosome changes, in the presence or absence of an underlying Mendelian disorder, has already been suggested. Our results and a review of the cytogenetic literature led us to postulate that mutations also causing FPD/AML may have a mutator effect that could give origin to myelodysplastic syndromes and acute myeloid leukemias through acquired chromosome changes.


Assuntos
Transtornos Plaquetários/genética , Aberrações Cromossômicas , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Leucemia Eritroblástica Aguda/genética , Transtornos Plaquetários/diagnóstico , Células da Medula Óssea/química , Células da Medula Óssea/metabolismo , Criança , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core , Análise Citogenética/métodos , Análise Mutacional de DNA/métodos , Proteínas de Ligação a DNA/genética , Progressão da Doença , Feminino , Marcadores Genéticos/genética , Humanos , Itália , Leucemia Eritroblástica Aguda/diagnóstico , Masculino , Monossomia/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Linhagem , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Trissomia/genética
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