Biomedical subjects

K Schaefer-Rego

Publications and source records attributed to K Schaefer-Rego.

7 recordsLinked to original sources

PubMed1991

ABL oncogene expression during erythroleukemia cell differentiation.

The translocation between chromosome 9 and chromosome 22 which creates the Philadelphia chromosome moves the ABL oncogene from its normal location on chromosome 9 and fuses it with a portion of the BCR gene on chromosome 22. This new BCR/ABL fusion gene generates a unique 8.7 kilobase (kb) RNA which codes for a new 210 kilodalton (kd, p210) protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the normal ABL protein. The human K562 cell line was derived from a patient with CML, and serves as one model for the regulation of expression of the ABL and BCR/ABL genes. This study examines the expression of the BCR/ABL fusion gene and the normal ABL gene in relation to differentiation and changes in proliferative state. The expression of both the normal ABL transcripts and the BCR/ABL fusion transcript decrease approximately ten-fold when the cells are induced to differentiate with hemin. In contrast, expression of the MYC oncogene is unaffected by hemin-induced differentiation. The results suggest that both ABL and BCR/ABL expression vary in proportion to the differentiation of the cells, but minimally if at all as a function of the cells' proliferative state.

Cell Differentiation↗

PubMed1988

Molecular heterogeneity of adult Philadelphia chromosome-positive acute lymphoblastic leukemia.

The (9;22) translocation which produces the Philadelphia (Ph1) chromosome activates the abl oncogene from chromosome 9 by recombination with the bcr gene from chromosome 22. This fusion gene is transcribed into a new 8.5-kilobase chimeric mRNA which is translated into a novel Mr 210,000 fusion protein which has a protein tyrosine kinase activity that is greatly increased in comparison to the activity of the normal abl protein. Studies from this laboratory and others have shown that virtually all patients with chronic myelogenous leukemia have this new bcr/abl fusion gene. In contrast to these findings in chronic myelogenous leukemia, a small number of patients with Ph1(+) acute lymphoblastic leukemia (ALL) have been studied and were found to lack the bcr/abl fusion gene [bcr(-)], but to have a new activation of abl, by recombination with an as yet undetermined region on chromosome 22. In this study, nine adults with Ph1(+)-ALL have been examined for evidence of a bcr/abl fusion gene. Of the nine patients, five have a bcr/abl recombination, whereas the remaining four patients do not. In contrast, the children studied to date have all been bcr(-). These data suggest that adults with Ph1(+)-ALL are a more heterogeneous group on a molecular level than are children, and that further studies will be required to determine the spectrum of molecular defects in patients with Ph1(+)-ALL, and the relationship of these various molecular defects to the clinical disease state of the individuals.

Adult↗

PubMed1987

Prenatal diagnosis of sickle hemoglobinopathies: the experience of the Columbia University Comprehensive Center for Sickle Cell Disease.

We report here an evaluation of 55 pregnancies at risk for a sickle hemoglobinopathy prenatally diagnosed by restriction-endonuclease analysis, with the endonucleases MstII and HpaI, of amniocyte DNA. The diagnosis was completed in all cases. Eleven fetuses were predicted to be affected, of which six were terminated. Forty-one of the 55 cases were confirmed. One false-negative was reported in a case predicted to be hemoglobin AS but that was determined to be hemoglobin SS at birth. We estimate that the 55 cases represent only 5% of the pregnancies at risk for a sickle hemoglobinopathy in the New York metropolitan area during the study period. We conclude that the prenatal diagnosis of sickle hemoglobinopathies by molecular methods is reliable. However, the efficiency of utilization and effectiveness of prenatal testing is dependent on the early prospective identification of couples at risk and on the education of communities concerning the significant morbidity of the sickle hemoglobinopathies and the reproductive choices now available to them.

Anemia, Sickle Cell↗

PubMed1987

CML patients in blast crisis have breakpoints localized to a specific region of the BCR.

Chronic myelogenous leukemia (CML) is associated with the Philadelphia (Ph) chromosome, which results from a reciprocal translocation between chromosomes 9 and 22. This activates the abl oncogene by moving it from chromosome 9 and combining it with sequence located on chromosome 22. The new fusion gene, with chromosome 22 sequence at its 5' end and chromosome 9-abl sequence at its 3' end, generates a new messenger RNA (mRNA) and protein that are implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 are concentrated within a 6 kilobase (kb) region termed the breakpoint cluster region (bcr). This study was designed to determine whether chronic-phase and blast crisis patients had identifiable differences in the structure of their Ph chromosomes. Restriction mapping of the chromosome 22 translocation breakpoints performed for 26 patients showed that the breakpoints of eight of the nine patients in blast crisis were in the 3' portion of the bcr, whereas the breakpoints in the 17 patients in the chronic phase were clustered in the 5' portion of the bcr. This suggests a strong correlation between a 3' bcr breakpoint and blast crisis in CML.

Blast Crisis↗

PubMed1986

Frequent and extensive deletion during the 9,22 translocation in CML.

Chromosomal translocation is one mechanism by which cellular oncogenes may be activated during tumorigenesis. The translocation of the abl oncogene to the Philadelphia chromosome in chronic myelogenous leukemia (CML) results in a new RNA transcript that fuses sequence from chromosome 22 to sequence from the abl oncogene. This RNA presumably codes for a new abl-related protein product found in CML, the activity of which is different from the normal abl protein. The molecular structure of the translocation varies from patient to patient, and the individual variation in RNA transcript and protein product remains to be defined. This report describes the frequent occurrence of chromosomal deletion within the 9q+ chromosome during these translocations. The location of the deletions suggests that some mechanism maintains the chromosomal breakpoint on the Philadelphia chromosome within a limited region. These deletions complicate the interpretation of Southern blots as a means of detecting the translocation.

Chromosome Deletion↗

PubMed1985

Variable breakpoints on the Philadelphia chromosome in chronic myelogenous leukemia.

The abl oncogene is translocated from chromosome 9 to 22 in the creation of the Philadelphia (Ph1) chromosome. This article describes new translocation breakpoints identified in two patients with chronic myelogenous leukemia using Southern blotting and cloned human DNA probes from chromosome 9. The translocation breakpoints on chromosome 9 in both of these patients lie closer to the human cellular abl (c-abl) gene, and the chromosome 22 breakpoints are distributed more widely than previously reported. These data help to define more clearly the chromosomal span of the breakpoints and indicate that some translocations include very little chromosome 9 sequence located 5' to the c-abl gene.

Chromosome Aberrations↗

PubMed1984

Dense cells in sickle cell anemia: the effects of gene interaction.

In an attempt to uncover potential genetic sources of the clinical diversity of sickle cell anemia, we have characterized homozygous SS patients in the following ways: percentage of dense red blood cells (% F4) as determined from Percoll-Stractan continuous density gradients, alpha gene deletion, average percentage of hemoglobin F (% HbF), hemoglobin in g/dL, age, and sex. We find that alpha 4 individuals have a higher % F4 (mean 24% +/- 15%) than alpha 3 individuals (mean 12% +/- 8%) (P less than .005). Multivariate analysis demonstrated a significant correlation among % F4 levels and alpha-gene number and % HbF, and an interaction between the last two variables. The other variables considered did not significantly alter this model. As reported before, with fewer samples, we find that in the first ten years of life of SS individuals, the frequency of alpha gene deletion is 17%, which is comparable to that in the general black population, while in the group over 20 years of age, the frequency rises to 49%, implying that alpha thalassemia is associated with longer survival. These results indicate that it is necessary to consider sickle cell anemia not only as a single gene defect, but also as a disease whose clinical expression is the result of a group of genes capable of interacting at the phenotypic level.

Adult↗