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F G Haluska

Publications and source records attributed to F G Haluska.

47 records · Page 3Linked to original sources
PubMed1987

The t(8;14) chromosome translocation of the Burkitt lymphoma cell line Daudi occurred during immunoglobulin gene rearrangement and involved the heavy chain diversity region.

Recent molecular analyses of Burkitt lymphomas carrying the t(8;14) chromosome translocation have indicated that a dichotomy exists regarding the molecular mechanisms by which the translocations occur. Most sporadic Burkitt tumors carry translocations that apparently arise due to mistakes in the immunoglobulin isotype-switching process. In contrast, there is evidence that the translocations of most endemic Burkitt lymphomas occur as a consequence of aberrant V-D-J recombination of variable, diversity, and joining gene segments, catalyzed by the recombinase enzymes. This phenomenon was first noted in follicular lymphomas and chronic lymphocytic leukemias of the B-cell lineage and has been described in T-cell malignancies as well. In each of these cases, analysis of the nucleotide sequence at chromosome breakpoints demonstrated the involvement of immunoglobulin heavy chain JH or T-cell-receptor alpha-chain J alpha gene segments in the translocation. We now have cloned and sequenced both the 8q- and 14q+ translocation breakpoints deriving from the t(8;14) translocation of the endemic Burkitt lymphoma line Daudi. Our data show that the translocation resulted from a reciprocal exchange between the DH region on chromosome 14 and sequences far 5' of the MYC protooncogene on chromosome 8. Features of the nucleotide sequences surrounding the breakpoint further implicate the V-D-J joining machinery in the genesis of chromosome translocations in endemic Burkitt lymphomas and, more generally, in other lymphoid malignancies as well.

Base Sequence↗
PubMed1987

Molecular mechanisms of chromosome translocation in human B- and T-cell neoplasia.

Our understanding of the molecular biology of many tumors is still rudimentary. The genes involved in most solid tumors, and the mechanisms giving rise to their activation, are virtually unknown. In contrast, for hematopoietic malignancies, we have identified several genes important in oncogenesis, and we understand in at least a limited sense the mechanisms by which translocations impart these genes with the capacity to support malignant growth. It is becoming increasingly apparent that these mechanisms involve very subtle changes in the pattern of gene expression. Similarly, the studies on the mechanisms of chromosome translocation described here underscore the proposition that malignancy may arise by slight perturbations of normal function. The enzymes that physiologically recombine Ig and TCR genes do so with high fidelity under normal circumstances. But occasionally misrecognition of target sequences may lead to chromosome translocation and neoplasia. A deeper understanding of this process will be facilitated by a more certain grasp of normal B- and T-lymphocyte differentiation and proliferation.

B-Lymphocytes↗
PubMed1986

Molecular genetics of B- and T-cell neoplasia.

Specific chromosomal translocations are involved in more than 80% of human B-cell neoplasms. In all these cases the neoplastic phenotype is apparently the consequence of reciprocal chromosomal translocations involving the loci for human immunoglobulin (Ig) chains and either well described cellular proto-oncogenes or putative proto-oncogenes. The juxtaposition of the proto-oncogenes to the Ig loci results in their transcriptional deregulation, because of their proximity to genetic elements within the Ig loci capable of activating gene transcription in cis over considerable chromosomal distances. Sequence analysis of the translocation breakpoints has provided important insights concerning the molecular mechanisms involved in chromosome translocation in B-cells. It appears that the reciprocal translocations contributing to B-cell neoplasia are catalyzed by the same enzymes that are involved in physiological Ig gene rearrangements. The analysis of human B-cell leukemias and lymphomas has also provided considerable information concerning the possible scenarios for B-cell neoplastic transformation. It is clear that the Epstein-Barr virus does not play a direct role in neoplastic transformation, but it may contribute by increasing the number of B-cells at risk of developing chromosome translocations during Ig gene rearrangements. Cytogenetic and molecular genetic analysis of T-cell malignancies is beginning to provide a very similar scenario for neoplastic transformation. The locus for the alpha chain of the T-cell receptor is directly involved, and it apparently juxtaposes to proto-oncogenes or to putative proto-oncogenes leading to their transcriptional deregulation. It seems quite likely that the enzyme system involved in rearrangements of the genes for the T-cell receptor plays a crucial role in the causation of these chromosomal translocations. Thus, the genetic basis of many human B- and T-cell neoplasms may be quite similar. For the future, the challenge resides in trying to characterize specifically the role of both old and new proto-oncogenes in B- and T-cell proliferation, normal and neoplastic.

B-Lymphocytes↗
PubMed1983

Experimental gypsy moth (Lymantria dispar) ophthalmia nodosa.

Ophthalmia nodosa is the nodular granulomatous inflammatory response of ocular tissue to caterpillar hairs. We experimentally simulated this condition by surgically implanting gypsy moth hairs in the rabbit cornea. We were not, however, able to produce ophthalmia nodosa solely by placing cilia in the rabbit cul-de-sac. The experimentally induced inflammation closely resembled human ophthalmia nodosa in both its clinical and histopathologic features.

Animals↗
PubMedDate not supplied

The t(8; 14) chromosomal translocation occurring in B-cell malignancies results from mistakes in V-D-J joining.

The reciprocal chromosome translocation, t(8;14), involving the heavy chain locus on chromosome 14 and the c-myc oncogene on chromosome 8 is a characteristic of the B-cell malignancies Burkitt's lymphoma and acute lymphoblastic leukaemia (ALL). We have cloned and sequenced the t(8; 14) breakpoints of an African Burkitt's lymphoma cell line, P3HR-1, and a pre-B cell ALL cell line, 380. In each case the region of chromosome 8 involved has recombined with a JH region on chromosome 14. The two sites of breakage on chromosome 8 lie within 70 base pairs (bp) of one another. At each joining site, sequences homologous to the signal sequences thought to be recognized by the V-D-J recombinase were identified, as were N regions. In B-cell chronic lymphocytic leukaemias (B-CLL) carrying the t(11; 14) chromosome translocation and in follicular lymphomas carrying the t(14; 18) translocation, the V-D-J recombinase is implicated in the mechanism of chromosomal translocations. We speculate that the same enzymatic mechanism is responsible for the t(8; 14) translocations in African Burkitt's lymphoma and pre-B cell ALL.

Base Sequence↗
PubMedDate not supplied

Adjuvant high-dose interferon alfa-2b in patients with high-risk melanoma.

We performed an analysis of toxicity and survival in stage III melanoma patients receiving adjuvant interferon alfa-2b (IFN). This was a retrospective single-arm analysis of 40 patients with stage III melanoma who received (IFN) administered at maximum tolerated doses of 20 mU/m2/day intravenously (i.v.) for 1 month and 10 mU/m2 three times per week subcutaneously (s.c.) for 48 weeks. Toxicity in our series is comparable to that experienced in the Eastern Cooperative Oncology Group (ECOG) 1684 trial, except for higher rates of dose-limiting myelosuppression and hepatotoxicity. All 40 patients experienced constitutional symptoms, but only 14/40 (35%) experienced grade 3 to 4 symptoms. Of the 40 patients, 36 (90%) experienced neurologic symptoms, but only seven (17.5%) experienced grade 3 to 4 neurotoxicity. Two patients stopped treatment because of severe psychiatric symptoms; one patient attempted suicide, and a psychosis developed in another. Thirty-nine (97.5%) patients experienced myelosuppression; 31 (77.5%) developing grade 3 to 4 myelosuppression. Hepatotoxicity was evident in 39 (97.5%) patients, and 26 (65%) experienced grade 3 to 4 hepatotoxicity. Three patients (7.5%) experienced mild renal toxicity. At a median follow-up of 27 months from initiation of therapy, there have been 19 relapses (47.5% disease-free survival [DFS]) and 10 deaths (75% OS) resulting from progression of disease. The DFS compares with the treatment arm in ECOG 1684 at 27 months, but overall survival is higher in our series of patients at the same time point. In a single program setting, IFN can be administered with similar side effects and outcome profiles seen in multi-institutional studies. Modifications in the induction regimen resulted in notably higher hematologic and hepatic toxicities but did not preclude administering further therapy and did not result in increased attrition rate among patients: only nine patients (22.5%) had their treatment stopped as a result of IFN-related toxicity. In comparison, 26% of patients had to have their treatment discontinued because of toxicity in ECOG 1684.

Adult↗