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1.
Ann Oncol ; 21(12): 2410-2419, 2010 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-20466745

RESUMEN

BACKGROUND: Patients with B-cell chronic lymphocytic leukemia (CLL) with 17p deletion respond poorly to chemotherapy. This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL in the various cytogenetic subgroups. PATIENTS AND METHODS: Data were collected from 105 consecutive, pretreated, cytogenetically defined patients who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS: The hierarchic incidence of cytogenetic abnormalities was: 13q deletion (as sole abnormality), 18%; trisomy 12, 13%; 11q deletion, 19%; 17p deletion, 33%; and none of these, 16%. Overall response rate (ORR) was 43% in the total cohort and 49% in the subgroup of 17p-deleted patients (n = 35). From the start of alemtuzumab monotherapy, median PFS in the total cohort and in the subgroup of 17p-deleted patients was 7.0 and 7.1 months, respectively. Median OS in the total cohort and in 17p-deleted patients was 32.8 and 19.1 months, respectively. The poor-risk group of patients with CLL (i.e. fludarabine resistant, 17p deletion; n = 20) showed encouraging ORR, PFS, and OS (35%, 7.0 and 19.2 months, respectively). CONCLUSIONS: Alemtuzumab was effective in treating patients with CLL across the cytogenetic categories evaluated, but there were differences. In patients with CLL with 17p deletion quite favorable ORR, PFS, and OS were achieved.


Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/uso terapéutico , Aberraciones Cromosómicas , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Anciano , Anciano de 80 o más Años , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Aberraciones Cromosómicas/estadística & datos numéricos , Progresión de la Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento
2.
Eur J Clin Invest ; 39(7): 568-75, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19453646

RESUMEN

BACKGROUND: The prognosis of chronic lymphocytic leukaemia (CLL) patients is largely determined by the karyotype of the malignant clone. We have investigated the gene expression profile associated with trisomy 12 (+12). DESIGN: Initially, unselected peripheral blood mononuclear cells of four patients with +12 were compared with 16 CLL controls using microarray analysis. RESULTS: were validated by quantitative real-time PCR with RNA from 61 patients (29 with +12, 32 CLL controls). Results Seven genes showing the strongest correlation with +12 in microarray analysis were selected for real-time PCR: HIP1R, MYF6, SLC2A6, CD9 (overexpressed); CD200, P2RY14, RASGRP3 (underexpressed). Four genes were significantly associated with +12: HIP1R (P<0.0001), MYF6 (P=0.007), P2RY14 (P=0.014), CD200 (P=0.028). Receiver Operating Characteristic curve analysis revealed that HIP1R expression was a highly sensitive and specific marker for +12 in CLL patients. MYF6 was exclusively expressed in normal or malignant B cells in peripheral blood but was poorly predictive for +12. As expected, a number of overexpressed genes are located on chromosome 12 (HIP1R, MYF6). Interestingly, both significantly underexpressed genes (P2RY14, CD200) reside on the long arm of chromosome 3 pointing to trans-repression in this region. CONCLUSIONS: Analysis of the molecular signature of trisomy 12 in CLL resulted in: (i) identification of a surrogate marker for PCR (HIP1R); (ii) observation of a gene dosage effect; and (iii) detection of specific underexpression of genes located on chromosome 3. These results should help to improve diagnosis and treatment decisions for patients with CLL and trisomy 12.


Asunto(s)
Cromosomas Humanos Par 12 , Leucemia Linfocítica Crónica de Células B/patología , Trisomía/patología , Cromosomas Humanos Par 12/genética , Femenino , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Cariotipificación , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Trisomía/genética
3.
Ann Oncol ; 19(5): 970-6, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18272915

RESUMEN

BACKGROUND: Early recognition of disease progression in low-risk myelodysplastic syndromes (MDS) is an important decision point concerning intensive therapies. In a screen program searching for dynamic prognostic determinants, we have identified lactate dehydrogenase (LDH) as a most suitable follow-up parameter. PATIENTS AND METHODS: LDH levels were serially determined in 221 patients with de novo MDS (median age 70 years, range 24-94). The increase in LDH was correlated with survival and acute myeloid leukemia (AML) evolution. RESULTS: Confirming previous data, an elevated LDH at diagnosis was found to be associated with an increased probability of AML evolution and decreased probability of survival (P < 0.05). In the follow-up, we found that in patients who progressed (to higher IPSS category or AML), LDH levels were significantly higher in the two 3-month period preceding progression compared with the initial two 3-month period (P < 0.005). In a subgroup of patients, the increase in LDH was accompanied or followed by other signs of disease progression, such as occurrence of thrombocytopenia or appearance of circulating blasts. In multivariate analyses, the LDH increase was found to be an independent prognostic variable. CONCLUSIONS: LDH is an interesting follow-up parameter in MDS, which may assist in early recognition of disease progression and thus help in risk stratification and patient selection for interventional therapies.


Asunto(s)
L-Lactato Deshidrogenasa/sangre , Síndromes Mielodisplásicos/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Médula Ósea/patología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/patología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/sangre , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia
4.
Hum Mutat ; 28(6): 599-612, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17311297

RESUMEN

We describe 94 pathogenic NF1 gene alterations in a cohort of 97 Austrian neurofibromatosis type 1 patients meeting the NIH criteria. All mutations were fully characterized at the genomic and mRNA levels. Over half of the patients carried novel mutations, and only a quarter carried recurrent minor-lesion mutations at 16 mutational warm spots. The remaining patients carried NF1 microdeletions (7%) and rare recurring mutations. Thirty-six of the mutations (38%) altered pre-mRNA splicing, and fall into five groups: exon skipping resulting from mutations at authentic splice sites (type I), cryptic exon inclusion caused by deep intronic mutations (type II), creation of de novo splice sites causing loss of exonic sequences (type III), activation of cryptic splice sites upon authentic splice-site disruption (type IV), and exonic sequence alterations causing exon skipping (type V). Extensive in silico analyses of 37 NF1 exons and surrounding intronic sequences suggested that the availability of a cryptic splice site combined with a strong natural upstream 3' splice site (3'ss)is the main determinant of cryptic splice-site activation upon 5' splice-site disruption. Furthermore, the exonic sequences downstream of exonic cryptic 5' splice sites (5'ss) resemble intronic more than exonic sequences with respect to exonic splicing enhancer and silencer density, helping to distinguish between exonic cryptic and pseudo 5'ss. This study provides valuable predictors for the splicing pathway used upon 5'ss mutation, and underscores the importance of using RNA-based techniques, together with methods to identify microdeletions and intragenic copy-number changes, for effective and reliable NF1 mutation detection.


Asunto(s)
Empalme Alternativo/genética , Genes de Neurofibromatosis 1 , Mutación , Neurofibromatosis 1/genética , Sitios de Empalme de ARN/genética , Adulto , Austria , Niño , Estudios de Cohortes , Simulación por Computador , Análisis Mutacional de ADN , Exones , Humanos , Neurofibromatosis 1/diagnóstico , Sensibilidad y Especificidad , Eliminación de Secuencia
5.
Leukemia ; 19(7): 1216-23, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15858619

RESUMEN

We investigated the pattern of lipoprotein lipase (LPL) expression in B-cell chronic lymphocytic leukemia (B-CLL) and assessed its prognostic relevance. Expression of LPL mRNA as well as protein was highly restricted to leukemic B cells. The intensity of intracellular immunoreactivity of LPL was higher in samples of patients with unmutated immunoglobulin heavy-chain variable region genes (IGV(H)) compared to those with mutated IGV(H) genes. LPL mRNA levels in peripheral blood mononuclear cells (PBMNC) from 104 CLL patients differed by 1.5 orders of magnitude between cases with mutated (N=51) or unmutated (N=53) IGV(H) (median: 1.33 vs 45.22 compared to normal PBMNC). LPL expression correlated strongly with IGV(H) mutational status (R=0.614; P<0.0001). High LPL expression predicted unmutated IGV(H) status with an odds ratio of 25.90 (P<0.0001) and discriminated between mutated and unmutated cases in 87 of 104 patients (84%). LPL expression was higher in patients with poor risk cytogenetics. High LPL expression was associated with a shorter treatment-free survival (median 40 vs 96 months, P=0.001) and a trend for a shorter median overall survival (105 months vs not reached). Our data establish LPL as a prognostic marker and suggest functional consequences of LPL overexpression in patients with B-CLL.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/enzimología , Lipoproteína Lipasa/biosíntesis , Aberraciones Cromosómicas , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Lipoproteína Lipasa/genética , Masculino , Persona de Mediana Edad , Mutación , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Riesgo , Factores de Riesgo , Análisis de Supervivencia
6.
Leukemia ; 19(12): 2223-31, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16193087

RESUMEN

The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian-German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.


Asunto(s)
Pruebas Enzimáticas Clínicas , L-Lactato Deshidrogenasa/sangre , Síndromes Mielodisplásicos/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Análisis Multivariante , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Tasa de Supervivencia
7.
Cancer Res ; 57(18): 3914-9, 1997 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-9307271

RESUMEN

We have identified a novel gene, GR6, located within the leukemia breakpoint region of 3q21, that is normally expressed in early fetal development but not in adult peripheral blood. GR6 is activated in the UCSD-AML1 cell line and in a leukemic sample, both of which carry a t(3;3)(q21;q26). In UCSD-AML1, we have also identified fusion transcripts between the ecotropic viral insertion site I (EVI1) gene in 3q26 and GR6 and between EVI1 and Ribophorin I that maps 30 kb telomeric to GR6 in 3q21. All fusions splice the 5' ends of the 3q21 genes into exon 2 of the EVI1 gene, an event that is similar to the normal intergenic splicing of MDS1-EVI1 and to those previously documented in leukemias with t(3;21) and t(3;12), in which acute myelogenous leukemia 1-EVI1 fusions and ETV6-EVI1 fusions, respectively, occur. The Ribophorin I-EVI1 fusion in particular may be a common occurrence in t(3;3).


Asunto(s)
Proteínas Sanguíneas/genética , Cromosomas Humanos Par 3 , Proteínas de Unión al ADN/genética , Proteínas Fetales , Genes , Leucemia/genética , Leucemia/virología , Proteínas Oncogénicas , Proteínas Proto-Oncogénicas , Proto-Oncogenes , Adulto , Empalme Alternativo , Secuencia de Aminoácidos , Secuencia de Bases , Inversión Cromosómica , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Exones , Expresión Génica , Humanos , Intrones , Linfocitos/fisiología , Proteína del Locus del Complejo MDS1 y EV11 , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , ARN Mensajero/genética , ARN Neoplásico/genética , Proteínas Recombinantes de Fusión/genética , Factores de Transcripción/genética , Translocación Genética , Integración Viral
8.
Cancer Res ; 54(12): 3278-87, 1994 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-8205550

RESUMEN

Medulloblastoma (MB) represents the most frequent malignant brain tumor of childhood but only a few cell lines and animal models of this primitive neuroectodermal tumor (PNET) have thus far been established. Using specific cell culture conditions, we were able to derive four human MB cell lines (MHH-MED-1-4) as well as a cell line from a spinal PNET (MHH-PNET-5). The four MB cell lines grew in suspension as floating cell aggregates or as slightly adherent cells. They consisted of undifferentiated cells that did not express markers of late neuronal or glial lineages such as neurofilaments or glial fibrillary acidic protein. They also lacked expression of major histocompatibility complex class I or II antigens on the cell surface. All four MB lines were positive for vimentin and neuron-specific enolase, whereas synaptophysin, neural cell adhesion molecule, galactocerebroside, GD2, GD3, and the A2B5 antigen were expressed inconsistently. In contrast, MHH-PNET-5 grew as adherent monolayer and expressed major histocompatibility complex class I antigen. By cytogenetic analysis, the lines were near diploid with clonal aberrations. The MB lines showed no losses of chromosome arm 17p by either cytogenetic or microsatellite analyses. The cell line MHH-MED-2 exhibited double minute chromosomes, amplification of the c-myc gene, and overexpression of c-myc mRNA and protein. N-myc, p53, and Rb protein expression were unaltered. All four continuously passaged MB cell lines and the MHH-PNET-5 line were xenotransplanted s.c. into athymic mice; three of four MB lines and the spinal PNET line gave rise to tumors. These cell lines will be useful tools for biological and preclinical studies on PNETs.


Asunto(s)
Neoplasias Cerebelosas/patología , Meduloblastoma/patología , Tumores Neuroectodérmicos Primitivos/patología , Neoplasias de la Médula Espinal/patología , Células Tumorales Cultivadas , Animales , División Celular/fisiología , Neoplasias Cerebelosas/química , Neoplasias Cerebelosas/genética , Genotipo , Humanos , Inmunohistoquímica , Cariotipificación , Meduloblastoma/química , Meduloblastoma/genética , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Tumores Neuroectodérmicos Primitivos/química , Tumores Neuroectodérmicos Primitivos/genética , Fenotipo , Ratas , Neoplasias de la Médula Espinal/química , Neoplasias de la Médula Espinal/genética
9.
J Clin Oncol ; 17(11): 3569-76, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10550156

RESUMEN

Acute myeloid leukemia (AML) at older age is associated with several biologic and clinical characteristics. Hence, it may arise from an early level of hematopoietic stem cells and has a high frequency of blast cells with multidrug resistance glycoprotein MDR1 expression and particularly a high incidence of poor prognostic karyotypes. These factors, rather than age per se, underlie the poorer outcome as compared with younger cases. Prospective randomized studies clearly demonstrate, however, that elderly patients benefit from more intensive induction therapy and particularly from full-dose application of anthracyclines and possibly also cytarabine. Hematopoietic growth factors accelerate the recovery from treatment-induced neutropenia and may improve the remission rate, remission duration, and even overall survival. New treatment strategies need to be developed, however, for poor-prognosis AML subtypes in order to further improve the therapeutic perspectives for elderly patients with AML.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Geriatría , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Algoritmos , Genes MDR , Factores de Crecimiento de Célula Hematopoyética/uso terapéutico , Humanos , Cariotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Pronóstico
10.
Leukemia ; 12(7): 1114-8, 1998 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-9665198

RESUMEN

Smad4 is a tumor suppressor that is inactivated in about 50% of pancreatic carcinomas. Mutations in this gene have also been found with variable, yet much lower frequency in other tumor types and were absent from a large number of samples from patients with hematological malignancies. Smad2 shows considerable sequence similarity with Smad4 and cooperates with it in the growth inhibitory TGF-beta pathway. Smad2 mutations have been found in a fraction of colon carcinomas and have been shown to impair the function of the corresponding proteins. However, only a few other tumor types have been screened for Smad2 mutations so far. Therefore, we analyzed 50 primary tumor samples from patients with acute lymphoid or myeloid leukemia (ALL or AML) and five cell lines of hematopoietic origin for alterations in the Smad2 gene. None of the specimens tested carried mutations in the conserved MH1 or MH2 domains of Smad2.


Asunto(s)
Proteínas de Unión al ADN/genética , Genes Supresores de Tumor , Leucemia Eritroblástica Aguda/genética , Leucemia Megacarioblástica Aguda/genética , Mutación , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transactivadores , Secuencia de Bases , Células de la Médula Ósea , Cromosomas Humanos Par 18 , Secuencia Conservada , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Eliminación de Gen , Humanos , Leucemia Eritroblástica Aguda/sangre , Leucemia Megacarioblástica Aguda/sangre , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , ARN Neoplásico/genética , Proteína Smad2 , Transcripción Genética , Células Tumorales Cultivadas
11.
Leukemia ; 10(12): 1891-6, 1996 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-8946927

RESUMEN

Thrombocytosis is a characteristic clinical feature in patients with myelocytic malignancies and chromosomal rearrangements of 3q21 and 3q26, sometimes called the '3q21q26 syndrome'. The function of thrombopoietin (TPO) in megakaryocytopoiesis and thrombopoiesis as well as its chromosomal location, marked TPO as a candidate gene for malignancies with 3q rearrangements combined with dysmegakaryopoiesis. In this study 12 cases with inv(3)(q21q26) or t(3;3)(q21;q26) were analyzed by means of PFGE, but no rearrangements near the TPO locus were detectable. Six YACs containing the TPO locus were isolated and characterized. By dual color in situ hybridization using a YAC from 3q26 containing the EVI1 gene and a YAC from the TPO locus, the localization of the human TPO gene could be refined to 3q27-q28 about 15-20 Mbp telomeric to the 3q26 breakpoints occurring in myeloid malignancies. TPO levels were analyzed in the serum of three patients and were found to be in the normal range. These results confirm the findings of two previous studies that thrombopoietin expression is not the main cause of thrombocytosis in the 3q21q26 syndrome.


Asunto(s)
Cromosomas Humanos Par 3 , Reordenamiento Génico , Trombocitosis/genética , Trombopoyetina/genética , Rotura Cromosómica , Mapeo Cromosómico , Cromosomas Artificiales de Levadura , Electroforesis en Gel de Campo Pulsado , Regulación de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Reacción en Cadena de la Polimerasa , Trombocitosis/sangre , Trombopoyetina/sangre
12.
Leukemia ; 7(10): 1663-6, 1993 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-8412330

RESUMEN

The karyotype of a boy with acute lymphoblastic leukemia (ALL) presenting with numerical and structural chromosome aberrations as determined by Giemsa-banding was further investigated using chromosome painting (CP). A translocation t(11;18)(q23;q21) was verified by this approach, and gain of chromosome 21 material due to a structural rearrangement was detected. Moreover, an unbalanced translocation of the long arm of chromosome 1, resembling the well known translocation t(1;19), was demonstrated to involve chromosome 22 instead of chromosome 19. Immunophenotyping of the leukemic blasts led to the diagnosis common ALL (CD19+, CD10+, clg-). Our case indicates that in ALL a translocation t(1;19) may be mimicked by other chromosomal rearrangements, and that CP may efficiently complement conventional cytogenetics in the exact characterization of the involved chromosomes.


Asunto(s)
Cromosomas Humanos Par 19/fisiología , Cromosomas Humanos Par 1/fisiología , Cromosomas Humanos Par 22/fisiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocación Genética/genética , Niño , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/fisiología , Cromosomas Humanos Par 18/fisiología , Cromosomas Humanos Par 21/fisiología , Sondas de ADN/genética , Reordenamiento Génico/genética , Humanos , Hibridación in Situ , Cariotipificación , Masculino
13.
Leukemia ; 6(5): 463-4, 1992 May.
Artículo en Inglés | MEDLINE | ID: mdl-1593911

RESUMEN

The Philadelphia (Ph) translocation is the most common cytogenetic abnormality in adult acute lymphoblastic leukemia (ALL) and is associated with an adverse prognosis. Using polymerase chain reaction (PCR) technology we recently observed a remarkably high incidence (55%) of BCR-ABL rearrangements in adult common ALL patients. In the present study we asked whether a subset of Ph-negative cALL, similarly to Ph-negative chronic myelocytic leukemia (CML) patients, exhibit BCR-ABL transcripts. PCR analysis of 58 adult Ph-negative cALL patients, including 47 cases with a normal karyotype revealed no evidence of chimeric BCR-ABL genes. We conclude that Ph-negative BCR/ABL-positive ALL is very rare entity if existing at all.


Asunto(s)
Proteínas de Fusión bcr-abl/genética , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Proteínas de Fusión bcr-abl/análisis , Genes abl , Humanos , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
14.
Leukemia ; 14(1): 68-76, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10637479

RESUMEN

To compare the clinical relevance of drug resistance factors in de novo acute myeloid leukemia (AML), we determined their relationship to both response to induction chemotherapy and survival of the patients in univariate as well as multivariate analyses. The drug resistance factors immunocytochemically studied in 111 patients at the time of diagnosis included the lung resistance protein (LRP), P-glycoprotein (P-gp), multidrug resistance protein (MRP1) and bcl-2. In the univariate analyses, age (P = 0.005), karyotype (P = 0.03), LRP (P = 0.003), P-gp (P = 0.02) and bcl-2 (P = 0.03) predicted for response to induction chemotherapy, whereas MRP1 had no predictive value. Age (P = 0.05), karyotype (P = 0.05) and LRP (P = 0.03) retained their predictive value in the multivariate logistic regression analyses. With regard to overall survival, age (P = 0. 008), karyotype (P = 0.006), LRP (P = 0.001) and P-gp (P = 0.01) were of prognostic value in the univariate Cox regression analyses but only age (P = 0.01), karyotype (P = 0.02) and LRP (P = 0.01) retained their prognostic significance in the multivariate analyses. A risk score based on the number of independent prognostic factors allowed division of patients into four groups with different outcome. In these groups, the complete remission rates were 93%, 75%, 47% and 33%, respectively, and median overall survival was 2.4, 1.2, 0.6 and 0.2 years, respectively. Thus, several drug resistance factors did predict outcome in the univariate analyses but LRP was the only drug resistance factor with independent predictive and prognostic significance. The proposed risk score might be useful for risk-adapted treatment in the future. Leukemia (2000) 14, 68-76.


Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Inmunohistoquímica , Cariotipificación , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Análisis de Supervivencia
15.
Leukemia ; 14(1): 93-9, 2000 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-10637482

RESUMEN

The recurring translocation t(10;11)(p13;q14) which is found in acute myeloid leukemia (AML) and in acute lymphoblastic leukemia (ALL) results in the fusion of the putative transcription factor AF10 to CALM encoding a clathrin assembly protein. Previous studies using mainly fluorescence in situ hybridization (FISH) analysis have shown that the CALM/AF10 rearrangement is found in immature acute myeloid leukemia (AML) of subtype M0 and M1 and in T cell ALL. In this study we analyzed the CALM/AF10 and AF10/CALM fusion mRNAs in a series of three patients with AML, one patient with T-ALL and two patients with precusor T lymphoblastic lymphoma. In all six patients the breakpoint in CALM is at the 3' end of the coding region (nt1926/1927 or nt 2091/2092). Three breakpoints could be identified in AF10 (nt 588/589, nt 882/883 and nt 978/979). These data demonstrate that the CALM/AF10 fusions found in patients differ only slightly with respect to the portion of AF10 present and that there is no obvious difference between the fusions found in AML patients compared to those found in patients with lymphoid malignancies. Leukemia (2000) 14, 93-99.


Asunto(s)
Reordenamiento Génico , Leucemia Mieloide/genética , Linfoma no Hodgkin/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 11 , Cartilla de ADN , ADN de Neoplasias , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Translocación Genética
16.
Leukemia ; 10(8): 1288-95, 1996 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8709633

RESUMEN

The translocation t(8;21)(q22;q22) occurs in 6 to 12 percent of patients with AML, and usually predicts a good response to chemotherapy with a high remission rate and a relatively long median survival. The influence of additional chromosome aberrations on the clinical outcome of patients with t(8;21) is unclear. We analyzed 51 cases of acute myeloid leukemia carrying a translocation t(8;21)(q22;q22); 23 female and 28 male patients. The complete remission rate was 92 percent and median overall survival was 52.4 months. The median overall survival of female patients was significantly worse than of male patients (37.2 months vs not reached, P = 0.025). Additional chromosome aberrations were detected in 41 patients at diagnosis (80 percent), 31 (61 percent) had lost a sex chromosome, seven (14 percent) showed a partial deletion of the long arm of chromosome 9 and in three patients (6 percent) a gain of chromosome 8 was observed. Whereas the loss of a sex chromosome had no influence on prognosis, a partial deletion of the long arm of chromosome 9 was an unfavorable prognostic factor. The median overall survival of the seven patients with del(9q) was only 12.5 months and thus significantly shorter than in patients with only t(8;21) or with t(8;21) and additional sex chromosome loss (median survival not reached: P = 0.0010).


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Cromosomas Humanos Par 9 , Leucemia Mieloide Aguda/genética , Translocación Genética , Enfermedad Aguda , Adolescente , Adulto , Anciano , Trasplante de Médula Ósea , Causas de Muerte , Niño , Preescolar , Aberraciones Cromosómicas , Bandeo Cromosómico , Mapeo Cromosómico , Femenino , Estudios de Seguimiento , Humanos , Cariotipificación , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Caracteres Sexuales , Aberraciones Cromosómicas Sexuales , Tasa de Supervivencia
17.
Leukemia ; 15(3): 377-84, 2001 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-11237060

RESUMEN

The current study was undertaken to search for differences in the biology of cytogenetic subgroups in patients with de novo acute myeloid leukemia (AML). In addition, factors influencing the metabolism of cytosine arabinoside (araC) as the key agent of antileukemic activity were assessed. Bone marrow aspirates from 91 patients with newly diagnosed AML in whom karyotypes were successfully obtained were analyzed: (1) for spontaneous proliferative activity by 3H-thymidine (3H-TdR) incorporation; (2) proliferative response to GM-CSF by in vitro incubation of blasts for 48 h with or without GM-CSF (100 U/ml) followed by an additional 4-h exposure to 3H-TdR (0.5 microCi/ml); and (3) parameters of araC metabolism comprising 3H-araC uptake in vitro and the activities of polymerase alpha (poly alpha), deoxycytidine kinase (DCK) and deoxycytidine deaminase (DCD). According to the results of chromosome analyses four cytogenetic subgroups were discriminated: (I) normal karyotypes (n = 38); (II) favorable karyotypes [t8;21), t(15;17), inv(16)] (n = 16); (III) unfavorable karyotypes [inv (3), -5, 5q-, t(6;9), +8, t (9;11), complex abnormalities] (n = 20); (IV) karyotypes of unknown prognostic significance (n = 17). Proliferative activity of leukemic blasts was significantly higher in favorable karyotypes (group II) as compared to cases with unfavorable cytogenetics (group III) with median values and range for 3H-TdR uptake in group II of 2.48 pmol/10(5) cells (0.28-25.8) and in group III of 0.51 pmol/10(5) cells (0.04-7.6) (P = 0.0096). The respective values in group I and group IV were 0.7pmol/10(5) cells (0.0-6.7) and 0.98 pmol/10(5) cells (0.0-4.0), respectively. Inversely, response to GM-CSF, as defined by an increase in 3H-TdR incorporation >1.5- fold over control values after 48h of GM-CSF exposure, was significantly lower for patients with a favorable karyotype (group II) as compared to group I (P = 0.04) and group III (P = 0.013). No significant differences between karyotype groups I, II, III and IV were found for 3H-araC incorporation, nor for the activities of poly alpha, DCK and DCD. These data demonstrate differences in the biology of cytogenetic subgroups in AML which may partly explain the well established differences in clinical outcome.


Asunto(s)
División Celular/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Leucemia Mieloide/patología , Enfermedad Aguda , Humanos , Cariotipificación , Resultado del Tratamiento
18.
Leukemia ; 14(12): 2059-63, 2000 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-11187893

RESUMEN

Recurrence of the disease is the major problem in the treatment of acute myeloid leukemia (AML). The majority of patients who achieve a second remission will ultimately relapse. In this retrospective single-center study, we have analyzed the outcome of patients with a second relapse and tried to define the prognostic factors in intensively treated patients. Of 534 patients with AML, 62 had a second relapse. Thirty-three received further intensive chemotherapy (CT). Eighteen patients (55%) achieved a third complete remission (CR). The early death (ED) rate was only 9%. The overall survival (OS) of treated vs untreated patients was 6.9 vs 1.3 months, respectively (P = 0.01). The major selection criteria for a third CT were a favourable (t(15;17),t(8;21),inv(16)) or normal karyotype, long (>11 months) second CR (P < or = 0.005) and no previous bone marrow transplantation (BMT)(P < 0.01). Favorable or normal karyotype, second CR >11 months, as well as no previous BMT (P < 0.01) were associated with the achievement of a third CR. Favorable (P < 0.005) or normal karyotype (P < 0.01), as well as a second CR >11 months (P < 0.005) were associated with prolonged survival after CT. The median OS for patients receiving CT with favorable or normal cytogenetics, a second CR > 11 months, but no previous BMT was 26.5 months. Five patients with favorable or normal karyotype achieved a fourth or fifth remission. We conclude that intensive CT is associated with a survival benefit and good quality of life if patients are properly selected.


Asunto(s)
Leucemia Mieloide/patología , Enfermedad Aguda , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Humanos , Leucemia Mieloide/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento
19.
Leukemia ; 10(6): 946-51, 1996 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-8667650

RESUMEN

Dysplastic hematopoiesis is the morphological hallmark of myelodysplastic syndromes. Dysplastic features in one or more lineages are also found frequently in bone marrow aspirates from patients with de novo AML and have been associated with an unfavorable prognosis. We asked whether dyshematopoiesis is an independent prognostic factor or an indicator of unrecognized secondary leukemia, identified by characteristic chromosomal abnormalities. Bone marrow aspirates from 102 patients with newly diagnosed AML were analyzed. Morphological analysis was obtained in all patients, flow cytometric analysis in 96 and successful cytogenetic analysis in 65 bone marrow aspirates. Dysgranulopoiesis (DysG) was found in 55, dysmegakaryopoiesis (DysM) in 32 and dyserythropoiesis (DysE) in 23 patients. Decreased side scatter signals of neutrophils in the flow cytometric analysis (DysS) were detected in 32 patients. DysG and DysS showed a highly significant correlation (P = 0.0005). DysG was an adverse negative prognostic factor for remission rate and event-free survival (P = 0.04, P = 0.02). An unfavorable karyotype was associated with a significantly lower chance for event-free survival (P = 0.002). The incidence of an unfavorable karyotype was significantly higher in patients with DysG (P = 0.01), DysM (P = 0.02) and DysS (P = 0.01). In patients with an unfavorable karyotype, dysplasia had no additional prognostic influence, however, in patients with a normal, favorable or prognostically uncertain karyotype DysG remained a predictor of lower remission rate (P = 0.03). We conclude that dysgranulopoiesis, dysmegakaryopoiesis and decreased side scatter signals of neutrophils are indicators of secondary leukemias in bone marrow aspirates from patients with de novo AML.


Asunto(s)
Médula Ósea/patología , Hematopoyesis , Leucemia Mieloide Aguda/patología , Aberraciones Cromosómicas , Supervivencia sin Enfermedad , Eritropoyesis , Citometría de Flujo , Granulocitos/patología , Humanos , Cariotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Megacariocitos/patología , Persona de Mediana Edad , Pronóstico , Inducción de Remisión
20.
Leukemia ; 8(8): 1318-26, 1994 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-8057667

RESUMEN

An inversion in the long arm of chromosome 3--inv(3)(q21q26)--or a translocation between both homologous chromosomes 3--t(3;3)(q21;q26)--is found specifically in myeloid neoplasias characterized by disturbances of thrombopoiesis and megakaryocyte development. Cytogenetic findings were correlated with clinical and hematological data in altogether 18 patients with acute nonlymphocytic leukemia (ANLL) and with inv(3) (13 patients) or t(3;3) (five patients), six of whom were male and 12 who were female. Chromosomal changes in addition to the 3q anomalies were demonstrated in 14 out of 18 patients, predominantly numerical and structural aberrations of chromosome 7 (12 cases) and/or abnormalities of 5q (five cases). Complex karyotype abnormalities were observed in six of 13 patients with inv(3), but in only one of five patients with t(3;3). In ten out of our 18 patients a preceding myelodysplastic syndrome (MDS) and/or exposure to mutagenic/carcinogenic agents had been established. In eight patients the morphology of ANLL blasts was immature (FAB subtype M1); in three patients ANLL-M4, and in two patients each ANLL-M5, M6, and M7 was diagnosed; in one patient with antecedent MDS the leukemic blasts were not classifiable according to the FAB criteria. A disturbed megakaryocyte development, characterized by an excess of micromegakaryocytes was observed in 14 patients, seven of them showed normal or elevated platelet counts as an unusual feature in patients with ANLL. The clinical course and outcome was extremely poor: 15 of 18 patients died within 10 months after the diagnosis of ANLL. Because of their missing response to conventional chemotherapy, patients with inv(3) or t(3;3) have to be estimated as at high risk. The characterization of genes affected by inv(3) or t(3;3) could help to elucidate molecular changes leading to impaired proliferation and differentiation of hematopoietic cells, also of the megakaryocytic lineage. Based on molecular genetic findings new therapeutical approaches could be designed.


Asunto(s)
Médula Ósea/patología , Aberraciones Cromosómicas , Trastornos de los Cromosomas , Inversión Cromosómica , Cromosomas Humanos Par 3 , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crónica/genética , Síndromes Mielodisplásicos/genética , Translocación Genética , Adulto , Anciano , Bandeo Cromosómico , Mapeo Cromosómico , Femenino , Eliminación de Gen , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Leucemia Mieloide Aguda/patología , Leucemia Mielomonocítica Crónica/patología , Masculino , Metafase , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología
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