RESUMEN
The basis for persistence of leukemic stem cells in the bone marrow microenvironment remains poorly understood. We present evidence that signaling cross-talk between α4 integrin and Abelson interactor-1 (Abi-1) is involved in the acquisition of an anchorage-dependent phenotype and drug resistance in Bcr-Abl-positive leukemia cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl-positive CD34+progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi-1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate -resistant leukemic cells. These results indicate that the α4-Abi-1 signaling pathway may mediate acquisition of the drug-resistant phenotype of leukemic cells.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas del Citoesqueleto/genética , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Microambiente Tumoral/efectos de los fármacos , Animales , Antígenos CD34/metabolismo , Adhesión Celular/efectos de los fármacos , Adhesión Celular/genética , Línea Celular Transformada , Proliferación Celular/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Integrina alfa4/metabolismo , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Complejo de la Endopetidasa Proteasomal/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
The fibroblast growth factor-receptor 3 (FGFR3) Lys650 codon is located within a critical region of the tyrosine kinase-domain activation loop. Two missense mutations in this codon are known to result in strong constitutive activation of the FGFR3 tyrosine kinase and cause three different skeletal dysplasia syndromes-thanatophoric dysplasia type II (TD2) (A1948G [Lys650Glu]) and SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) syndrome and thanatophoric dysplasia type I (TD1) (both due to A1949T [Lys650Met]). Other mutations within the FGFR3 tyrosine kinase domain (e.g., C1620A or C1620G [both resulting in Asn540Lys]) are known to cause hypochondroplasia, a relatively common but milder skeletal dysplasia. In 90 individuals with suspected clinical diagnoses of hypochondroplasia who do not have Asn540Lys mutations, we screened for mutations, in FGFR3 exon 15, that would disrupt a unique BbsI restriction site that includes the Lys650 codon. We report here the discovery of three novel mutations (G1950T and G1950C [both resulting in Lys650Asn] and A1948C [Lys650Gln]) occurring in six individuals from five families. Several physical and radiological features of these individuals were significantly milder than those in individuals with the Asn540Lys mutations. The Lys650Asn/Gln mutations result in constitutive activation of the FGFR3 tyrosine kinase but to a lesser degree than that observed with the Lys540Glu and Lys650Met mutations. These results demonstrate that different amino acid substitutions at the FGFR3 Lys650 codon can result in several different skeletal dysplasia phenotypes.
Asunto(s)
Enfermedades del Desarrollo Óseo/genética , Codón/genética , Lisina/genética , Mutación Missense/genética , Proteínas Tirosina Quinasas , Receptores de Factores de Crecimiento de Fibroblastos/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Secuencia de Bases , Estatura , Enfermedades del Desarrollo Óseo/fisiopatología , Huesos del Carpo/anomalías , Niño , Preescolar , Activación Enzimática , Exones/genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Fosforilación , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos , Receptores de Factores de Crecimiento de Fibroblastos/química , Receptores de Factores de Crecimiento de Fibroblastos/metabolismoRESUMEN
To further characterize the clinical, radiographic and chondro-osseous morphologic changes in the Desbuquois syndrome, 7 patients from three sibships are described. They all had prenatal onset severe rhizomelic and mesomelic shortness with marked joint laxity and marked micrognathia. Radiographic changes were distinct, consisting of a supernumerary ossification center between the proximal phalanx of the index finger and the second metacarpal, and variable thumb changes. The femoral necks showed enlargement of the lesser trochanter with metaphyseal breaking, producing a characteristic "monkey wrench" (Swedish key) appearance. Growth plate cartilage showed dilated cisterns of rough endoplasmic reticulum in reserve zone chondrocytes. Three of the 7 cases were diagnosed prenatally by second trimester ultrasound and one case by fetoscopy. This syndrome exhibits significant phenotypic variability and must be differentiated from the Catel-Manzke syndrome which exhibits similar radiographic changes in the hands.
Asunto(s)
Huesos/anomalías , Enanismo/patología , Inestabilidad de la Articulación/patología , Adolescente , Preescolar , Enanismo/diagnóstico por imagen , Femenino , Placa de Crecimiento/patología , Humanos , Cuerpos de Inclusión/patología , Lactante , Inestabilidad de la Articulación/diagnóstico por imagen , Masculino , Radiografía , SíndromeRESUMEN
We have studied three patients, one with extensive polyposis of the colon, who have constitutional interstitial deletions of the long arm of chromosome 5. High-resolution banding studies indicated that the deletion in the patient with polyposis spans the region 5q21-q22, which includes APC, a gene involved in familial adenomatous polyposis and sporadic colon cancer. Molecular analysis with probes for sequences flanking APC confirmed this conclusion. The deletions in the other two patients, who are too young to have developed polyposis, had breakpoints within this region, precluding the use of cytogenetic analysis alone in making definitive predictions about their risks. Molecular studies resolved the uncertainty; in situ and quantitative Southern hybridizations of four probes for polymorphic segments revealed that one of the patients has a deletion of MCC, a gene which is approximately 150 kb proximal to APC, and two flanking markers. He is at increased risk for polyposis, while the other patient is not. The physical descriptions of these patients, in conjunction with cases in the literature, begin to allow delineation of two distinct 5q-syndromes. These studies also provide precise physical mapping data for D5S71, D5S81, D5S84, and MCC on 5q.
Asunto(s)
Anomalías Múltiples/genética , Poliposis Adenomatosa del Colon/genética , Deleción Cromosómica , Cromosomas Humanos Par 5 , Adolescente , Adulto , Secuencia de Bases , Southern Blotting , Sondas de ADN/genética , Femenino , Marcadores Genéticos/genética , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Datos de Secuencia Molecular , SíndromeRESUMEN
Cytogenetic and molecular techniques were employed to determine the origin of marker chromosomes in five patients with mosaic 45,X karyotypes. The markers were shown to be derived from the X chromosome in three female patients and from the Y chromosome in one female and one male. One of the female patients, with a very small, X-derived ring chromosome, had additional phenotypic abnormalities not typically associated with Turner syndrome. In this patient, both the ring and the normal X chromosomes replicated early; perhaps the unusual phenotype is the result of both chromosomes remaining transcriptionally active. These studies illustrate the power of resolution and utility of combined cytogenetic and molecular approaches to some clinical cases.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Mosaicismo , Síndrome de Turner/genética , Cromosoma X , Adolescente , Adulto , Southern Blotting , Preescolar , Bandeo Cromosómico , ADN/genética , ADN/aislamiento & purificación , Femenino , Marcadores Genéticos , Humanos , Lactante , Cariotipificación , Linfocitos/patología , MasculinoRESUMEN
A previously unreported isodicentric chromosome 18 was discovered in an abnormal infant boy whose mosaic karyotype was 46,XY/46,XY,-18,+idic(18)(q12.2). His constellation of congenital anomalies was typical of the 18q-syndrome. The clinical and cytogenetic characteristics of this patient are reported, and the literature concerning isochromosomes of 18 is reviewed.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 18 , Mosaicismo , Bandeo Cromosómico , Humanos , Recién Nacido , Cariotipificación , Masculino , Fenotipo , SíndromeRESUMEN
A family with an unusual variant of chromosome 16 is presented. The mother and son both with additional material present in the short arm of chromosome 16 adjacent to the centromere are phenotypically normal. The extra C-band negative region has been shown not to be composed of alpha satellite DNA. The literature regarding other familial cases of what appears to be the same variant of chromosome 16 is reviewed.
Asunto(s)
Cromatina/ultraestructura , Aberraciones Cromosómicas , Cromosomas Humanos Par 16 , Adulto , Bandeo Cromosómico , Femenino , Humanos , Recién Nacido , Cariotipificación , Masculino , Fenotipo , EmbarazoRESUMEN
A diagnosis of 45,X/48,XYYY was made antenatally. Counseling this case was hampered by the paucity of literature describing the phenotype of patients with this chromosome constitution. The fetus had ambiguous external genitalia, a horseshoe kidney, a cerebral cortical cyst and arachnodactyly.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Genitales/anomalías , Aberraciones Cromosómicas Sexuales/diagnóstico , Cromosoma Y , Adulto , Femenino , Feto , Humanos , Masculino , Mosaicismo/genética , Embarazo , Diagnóstico PrenatalRESUMEN
Patient, contact data, collected by two first year pediatric residents, separated in time by 25 years, were compared, and it is concluded that pediatric residency has undergone major changes throughout the past quarter century. Pediatric training has increased in length and includes more female residents. The overall intensity of patient care pediatric residents provide has increased. Children with chronic disorders that were often lethal conditions 25 years ago now make up a large portion of pediatric admissions to teaching hospitals.
Asunto(s)
Internado y Residencia/tendencias , Pediatría/educación , Niño , Preescolar , Enfermedad Crónica , Femenino , Hospitales de Enseñanza , Humanos , Lactante , Recién Nacido , Masculino , Estados UnidosRESUMEN
Chemotherapy plus surgery is feasible and potentially effective in selected patients with small cell lung cancer (SCLC) and provides a unique opportunity to study SCLC early in its biological history. The in vitro characteristics of a SCLC cell line derived from a resected lung primary tumor after treatment with 3 courses of chemotherapy is described. The original SCLC cell line UMC-SCLC-1 exhibited features of classic SCLC with typical morphology and growth characteristics, high levels of dopa decarboxylase, bombesin-like peptides, neuron-specific enolase and calcitonin, and the presence of neurosecretory granules and demonstrated the deletion of the short arm of chromosome 3. After multiple passages, UMC-SCLC-1 gradually changed its culture characteristics to a cell line, UMC-SCLC-1A, with morphological features of large cell anaplastic carcinoma, an altered growth pattern, decrease in calcitonin, and increase in radioresistance but retained the other biochemical markers of classic SCLC (bombesin and dopa decarboxylase production). Serial DNA content analyses showed that increased aneuploidy during continuous culture in vitro was associated with the morphological changes. Both UMC-SCLC-1 and UMC-SCLC-1A demonstrated the deletion of chromosome 3p, amplification and abundant expression of N-myc, and increased expression of c-raf. Chemotherapy sensitivities were stable throughout multiple passages and correlated with in vivo response. UMC-SCLC-1A represents a unique SCLC cell line with heterogeneous properties of both classic and morphological variant SCLC cell lines. In addition, the characteristic deletion of 3p, previously described in cultures derived from metastatic lesions and heavily pretreated patients, is seen in a primary lesion early in the natural history of SCLC.
Asunto(s)
Carcinoma de Células Pequeñas/patología , Deleción Cromosómica , Cromosomas Humanos Par 3 , Neoplasias Pulmonares/patología , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/terapia , Línea Celular , ADN/análisis , Femenino , Amplificación de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Persona de Mediana Edad , Proto-OncogenesRESUMEN
Since the original description of solitary rectal ulcer by Cruveilheir in 1830, about 250 cases have been reported (1). The condition most frequently presents in adults between 30 and 50 years of age. There are very few pediatric case reports and none have come from North America. We report here a 13-year-old boy with solitary rectal ulcer syndrome and a review of the pediatric experience with this rare condition.