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1.
Genes (Basel) ; 14(11)2023 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-38003028

RESUMEN

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.


Asunto(s)
Enfermedad Granulomatosa Crónica , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Masculino , Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Donante no Emparentado , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/patología , Translocación Genética
2.
Blood ; 138(7): 557-570, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-34010415

RESUMEN

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.


Asunto(s)
Proliferación Celular , Leucemia Mieloide Aguda/metabolismo , Células Madre Mesenquimatosas/metabolismo , Transcriptoma , Canales de Calcio Tipo L/metabolismo , Dihidropiridinas/farmacología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Células Madre Mesenquimatosas/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Células Tumorales Cultivadas , Microambiente Tumoral
5.
Oncotarget ; 8(66): 109915-109923, 2017 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-29299118

RESUMEN

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.
Artículo en Inglés | MEDLINE | ID: mdl-25270907

RESUMEN

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.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Translocación Genética , Adolescente , Adulto , Niño , Preescolar , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 6/metabolismo , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 7/metabolismo , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Receptores de Hialuranos/biosíntesis , Receptores de Hialuranos/genética , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Tasa de Supervivencia , Trisomía/genética
8.
Int J Hematol ; 99(2): 208-12, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24338706

RESUMEN

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.


Asunto(s)
Enfermedades en Gemelos/terapia , Rechazo de Injerto/fisiopatología , Supervivencia de Injerto , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mielomonocítica Juvenil/terapia , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Enfermedades en Gemelos/diagnóstico , Enfermedades en Gemelos/inmunología , Enfermedades en Gemelos/metabolismo , Resultado Fatal , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Rechazo de Injerto/inmunología , Humanos , Lactante , Leucemia Mielomonocítica Juvenil/diagnóstico , Leucemia Mielomonocítica Juvenil/inmunología , Leucemia Mielomonocítica Juvenil/metabolismo , Masculino , Pronóstico , Inducción de Remisión , Trasplante Homólogo , Resultado del Tratamiento , Gemelos Monocigóticos
9.
Leuk Res ; 37(8): 928-35, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23735857

RESUMEN

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.


Asunto(s)
Genómica/métodos , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Hibridación Fluorescente in Situ/métodos , Cariotipo , Masculino , Polimorfismo de Nucleótido Simple , Pronóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
12.
Blood ; 117(26): 7102-11, 2011 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-21551233

RESUMEN

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.


Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Reordenamiento Génico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Niño , Preescolar , Cromosomas Humanos Par 19 , Cromosomas Humanos Par 8 , Estudios de Cohortes , Análisis Citogenético , Femenino , Estudios de Asociación Genética , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Masculino , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Translocación Genética , Trisomía
13.
Pediatr Blood Cancer ; 55(3): 446-51, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20658615

RESUMEN

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.


Asunto(s)
Linfoma Anaplásico de Células Grandes/genética , Adolescente , Adulto , Quinasa de Linfoma Anaplásico , Niño , Aberraciones Cromosómicas , Diploidia , Femenino , Humanos , Masculino , Monosomía , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas Receptoras , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Translocación Genética , Trisomía
14.
Blood ; 114(12): 2489-96, 2009 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-19528532

RESUMEN

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.


Asunto(s)
Cromosomas Humanos Par 11/genética , Reordenamiento Génico , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Translocación Genética , Niño , Mapeo Cromosómico , Cromosomas Humanos Par 9/genética , Supervivencia sin Enfermedad , N-Metiltransferasa de Histona-Lisina , Humanos , Hibridación Fluorescente in Situ , Agencias Internacionales , Cariotipificación , Pronóstico , Estudios Retrospectivos
15.
Cancer Chemother Pharmacol ; 64(6): 1235-51, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19363609

RESUMEN

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.


Asunto(s)
Apoptosis/efectos de los fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacología , Moduladores de Tubulina/farmacología , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Caspasa 3/metabolismo , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dacarbazina/química , Dacarbazina/uso terapéutico , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Humanos , Células Jurkat , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Microtúbulos/química , Microtúbulos/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosfatidilserinas/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Temozolomida , Tubulina (Proteína)/química , Moduladores de Tubulina/química , Moduladores de Tubulina/uso terapéutico , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismo
16.
Genes Chromosomes Cancer ; 48(1): 22-38, 2009 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18803328

RESUMEN

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.


Asunto(s)
Polimorfismo de Nucleótido Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Proteínas de Unión al Calcio/genética , Niño , Preescolar , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 21/genética , Femenino , Eliminación de Gen , Regulación Leucémica de la Expresión Génica , Genes p16 , Marcadores Genéticos , Humanos , Lactante , Péptidos y Proteínas de Señalización Intercelular/genética , Proteína Jagged-1 , Masculino , Proteínas de la Membrana/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/clasificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Proteínas Serrate-Jagged , Proteína Smad1/genética , Disomía Uniparental , Proteína ETS de Variante de Translocación 6
17.
Pediatr Blood Cancer ; 52(3): 357-63, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19061215

RESUMEN

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.


Asunto(s)
Crisis Blástica/diagnóstico , Síndromes Mielodisplásicos/diagnóstico , Adolescente , Antígenos CD34/análisis , Antígenos CD34/inmunología , Antígenos CD7/análisis , Antígenos CD7/inmunología , Crisis Blástica/metabolismo , Crisis Blástica/patología , Diferenciación Celular , Niño , Preescolar , Femenino , Humanos , Inmunofenotipificación , Masculino , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , Estadificación de Neoplasias , Células Precursoras de Linfocitos B/citología , Células Precursoras de Linfocitos B/inmunología , Pronóstico , Tasa de Supervivencia
18.
Mol Cancer ; 7: 80, 2008 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-18947387

RESUMEN

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.


Asunto(s)
Médula Ósea/metabolismo , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 2/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , ARN no Traducido/genética , Translocación Genética , Adolescente , Secuencia de Bases , Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Masculino , Datos de Secuencia Molecular , ARN no Traducido/metabolismo
19.
Am J Surg Pathol ; 31(3): 454-9, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17325488

RESUMEN

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.


Asunto(s)
Neoplasias Abdominales/patología , Carcinoma de Células Pequeñas/secundario , Leiomiosarcoma/patología , Proteínas de Fusión Oncogénica/metabolismo , Neoplasias Abdominales/genética , Neoplasias Abdominales/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/metabolismo , Niño , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 22 , Análisis Citogenético , Desmina/metabolismo , Supervivencia sin Enfermedad , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/metabolismo , Masculino , Neoplasias Primarias Secundarias , Proteínas de Fusión Oncogénica/genética , ARN Neoplásico/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Translocación Genética
20.
Genes Chromosomes Cancer ; 40(3): 165-71, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15138996

RESUMEN

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.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas/genética , Aberraciones Cromosómicas , Heterogeneidad Genética , Predisposición Genética a la Enfermedad/genética , Leucemia Eritroblástica Aguda/genética , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Células de la Médula Ósea/química , Células de la Médula Ósea/metabolismo , Niño , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 8/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Análisis Citogenético/métodos , Análisis Mutacional de ADN/métodos , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Femenino , Marcadores Genéticos/genética , Humanos , Italia , Leucemia Eritroblástica Aguda/diagnóstico , Masculino , Monosomía/genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Linaje , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Trisomía/genética
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