Rosai-Dorfman disease following bone marrow transplantation for pre-B cell acute lymphoblastic leukemia.

A child with acute pre-B cell lymphoblastic leukemia underwent haploidentical bone marrow transplantation (BMT) after first relapse. Approximately 8 months after the BMT, he developed a soft tissue mass overlying a defect in the left frontal bone. He was found to have several additional osteolytic lesions but no evidence of lymphadenopathy or organomegaly. A biopsy of the presenting lesion demonstrated a polymorphous infiltrate composed predominantly of S-100 protein and CD68 immunoreactive histiocytic cells. Together with the presence of emperipolesis, the process was interpreted as Rosai-Dorfman (R-D) disease. He received chemotherapy with vinblastine, prednisone, 6-mercaptopurine and methotrexate and has been in remission for over 4 years. Only one previous example of acute lymphoblastic leukemia in childhood has been reported with R-D disease.

Developmental regulation of Zbu1, a DNA-binding member of the SWI2/SNF2 family.

The SWI2/SNF2 gene family has been implicated in a wide variety of processes, involving regulation of DNA structure and chromatin configuration, mitotic chromosome segregation, and DNA repair. Here we report the characterization of the Zbu1 gene, also known as HIP116, located on human chromosome band 3q25, which encodes a DNA-binding member of this superfamily. Zbu1 was isolated in this study by its affinity for a site in the myosin light chain 1/3 enhancer. The protein has single-stranded DNA-dependent ATPase activity, includes seven helicase motifs, and a RING finger motif that is shared exclusively by the RAD5, spRAD8, and RAD16 family members. During mouse embryogenesis, Zbu1 transcripts are detected relatively late in fetal development and increase in neonatal stages, whereas the protein accumulates asynchronously in heart, skeletal muscle, and brain. In adult human tissues, alternatively spliced Zbu1 transcripts are ubiquitous with highest expression in these tissues. Gene expression is also dramatically induced in human tumor lines and in Li-Fraumeni fibroblast cultures, suggesting that it is aberrantly regulated in malignant cells. The developmental profile of Zbu1 gene expression and the association of the protein with a tissue-specific transcriptional regulatory element distinguish it from other members of the SWI2/SNF2 family and suggest novel roles for the Zbu1 gene product.

Chromosomal localization and cDNA cloning of the human DBP and TEF genes.

We have isolated cDNA and genomic clones and determined the human chromosome positions of two genes encoding transcription factors expressed in the liver and the pituitary gland: albumin D-site-binding protein (DBP) and thyrotroph embryonic factor (TEF). Both proteins have been identified as members of the PAR (proline and acidic amino acid-rich) subfamily of bZIP transcription factors in the rat, but human homologues have not been characterized. Using a fluorescence in situ hybridization technique, the DBP locus was assigned to chromosome 19q13, and TEF to chromosome 22q13. Each assignment was confirmed by means of human chromosome segregation in somatic cell hybrids. Coding sequences of DBP and TEF, extending beyond the bZIP domain to the PAR region, were highly conserved in both human-human and interspecies comparisons. Conservation of the exon-intron boundaries of each bZIP domain encoding exon suggested derivation from a common ancestral gene. DBP and TEF mRNAs were expressed in all tissues and cell lines examined, including brain, lung, liver, spleen, and kidney. Knowledge of the human chromosome locations of these PAR proteins will facilitate studies to assess their involvement in carcinogenesis and other fundamental biological processes.

Quality of survival among children treated for brain stem glioma.

In order to describe the status of long-term survivors of brain stem glioma, neuropsychological and behavioral measures were obtained a median of 2.5 (range 1.5-5.6) years after diagnosis from 16 survivors of 51 consecutively diagnosed children with brain stem glioma between 1983 and 1991. Among 11 children with dorsally exophytic tumors, 7 were treated with surgery alone (SRG) and 4 received conventionally fractionated local cranial radiation therapy (CFRT; 54-56 Gy) to the brain stem following surgery, 3 of these because of recurrent disease. Five others with diffusely infiltrative brain stem tumors received hyperfractionated radiation therapy (HFRT; 70.2 Gy) to the brain stem; 4 following biopsy or limited resection and 1 without prior surgery. IQs of children in the CFRT (mean 89, SD 24.4) and HFRT (mean 85, SD 12.7) groups were not significantly different. Children in the SRG group had significantly higher IQs (mean 100, SD 11.0) and fewer neurologic deficits than those who had received CFRT or HFRT. However, after statistically controlling for severity of neurologic deficits, treatment had no effect on IQ. The severity of residual neurologic deficits accounted for 42% of the variance in IQ scores; children with fewer neurologic problems scored higher. Additional studies are required to evaluate the potential neuropsychological benefits of equivalent total doses of HFRT compared to CFRT.

Predominance of pilocytic histology in dorsally exophytic brain stem tumors.

We report the magnetic resonance imaging (MRI) and clinico-histologic characterization of dorsally exophytic brain stem gliomas (DEBSGs). Between 1983 and 1991, 12 of 51 patients evaluated for the diagnosis of brain stem glioma were found to have DEBSGs emanating from the pons, pontomedullary junction or medulla. Eleven of the 12 patients had classic juvenile pilocytic astrocytomas. Unlike most other brain stem tumors, these patients were young (median 38 months, range 17-75), had a relatively long duration of symptoms (median 7 months, range 2-24) and displayed signs of increased intracranial pressure with limited cranial nerve paresis, absence of pyramidal tract findings, and near normal brain stem auditory-evoked potentials. MRI characteristically showed sharply demarcated lesions with decreased signal intensity on T1, and increased intensity on T2 sequences. Except for cystic areas, these tumors showed bright, uniform enhancement after gadolinium-DTPA. In all patients, 50-100% of the tumor volume could be resected. Three of 10 patients who received no immediate postoperative treatment eventually demonstrated disease progression, and 2 patients with subtotal resections who were treated with radiation and/or chemotherapy postoperatively remain disease-free for extended periods of time. The only death occurred in the 1 patient treated with chemotherapy who died of secondary leukemia. The overall and progression-free survival of these patients at 2 years is 100 and 67% as compared to 18 and 21%, respectively, for other concomitantly treated nonexophytic brain stem gliomas.2+ the ability to achieve significant degrees of resection.

Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas.

The 34-kilodalton cyclin-dependent kinase, p34cdk4, is a major catalytic subunit of mammalian D-type cyclins, which act during the G1 phase of the cell cycle to enforce the decision of cells to enter S phase. A murine complementary DNA clone was used to clone the cognate human CDK4 gene, which was localized to human chromosome 12, band q13, by fluorescence in situ hybridization. Because this chromosomal band contains the GLI and MDM2 genes, which are frequently amplified in human sarcomas, we analyzed CDK4 copy number and expression in a panel of sarcoma cell lines. An osteosarcoma cell line, OsACL, manifested a 25-fold increased copy number of CDK4, amplified concordantly with both GLI and MDM2, whereas a rhabdomyosarcoma cell line, SJRH30, was found to have an amplicon that included CDK4 and GLI but not MDM2. CDK4 mRNA and protein were overexpressed in both cell lines, and nucleotide sequencing analysis indicated that the gene had not sustained mutations. These observations provide the first evidence for amplification of a gene encoding a cell division cycle protein kinase, complement recent data indicating that genes encoding D-type cyclins are targets of chromosomal rearrangement and gene amplification in tumor cells, and suggest that CDK4 amplification might contribute to oncogenesis.