Finding a role for PML in APL pathogenesis: a critical assessment of potential PML activities.

In normal mammalian cells the promyelocytic leukemia protein (PML) is primarily localized in multiprotein nuclear complexes called PML nuclear bodies. However, both PML and PML nuclear bodies are disrupted in acute promyelocytic leukemia (APL). The treatment of APL patients with all-trans retinoic acid (ATRA) results in clinical remission associated with blast cell differentiation and reformation of the PML nuclear bodies. These observations imply that the structural integrity of the PML nuclear body is critically important for normal cellular functions. Indeed, PML protein is a negative growth regulator capable of causing growth arrest in the G(1) phase of the cell cycle, transformation suppression, senescence and apoptosis. These PML-mediated, physiological effects can be readily demonstrated. However, a discrete biochemical and molecular model of PML function has yet to be defined. Upon first assessment of the current PML literature there appears to be a seemingly endless list of potential PML partner proteins implicating PML in a variety of regulatory mechanisms at every level of gene expression. The purpose of this review is to simplify this confusing field of research by using strict criteria to deduce which models of PML body function are well supported.

PML RING suppresses oncogenic transformation by reducing the affinity of eIF4E for mRNA.

The promyelocytic leukemia protein PML is organized into nuclear bodies which mediate suppression of oncogenic transformation and of growth. The biochemical functions of PML bodies are unknown, despite their involvement in several human disorders. We demonstrate that eukaryotic initiation factor 4E (eIF4E) directly binds the PML RING, a domain required for association with bodies and for suppression of transformation. Nuclear eIF4E functions in nucleocytoplasmic transport of a subset of transcripts including Cyclin D1. Present studies indicate that some PML requires the evolutionarily older eIF4E protein for association with nuclear bodies. Further more, PML RING modulates eIF4E activity by drastically reducing its affinity for its substrate, 5' m(7)G cap of mRNA. We demonstrate that eIF4E requires cap binding for transport of Cyclin D1 mRNA and subsequent transformation activity. Additionally, PML reduces the affinity of eIF4E for m(7)G mRNA cap, causing a reduction in Cyclin D1 protein levels and consequent transformation inhibition. PML is the first factor shown to modulate nuclear eIF4E function. These findings provide the first biochemical framework for understanding the transformation suppression activity of PML.

Leukotriene B4 modulates in vivo expression of delayed-type hypersensitivity by a receptor-mediated mechanism: regulation by lipoxin A4.

Leukotriene B4 (LTB4) is a potent proinflammatory arachidonic acid metabolite whose actions are mediated by specific receptors. Recent characterization of a high-affinity LTB4 receptor on the surface of guinea pig CD4+ T lymphocytes prompted examination of a possible role of LTB4 in modulating in vivo expression of delayed-type hypersensitivity (DTH) to tuberculin (PPD). In the absence of PPD, intradermal injections of LTB4 or LTB4/LTD4 receptor antagonists did not elicit delayed-onset erythema at 24 h. When injected together with PPD, LTB4 (1 fmol to 1 pmol) caused a significant 25 to 30% decrease in DTH expression, whereas LTB4 receptor antagonists SC-41930, LY-223982, ONO-4057 (0.1-10 nmol), caused a highly significant (P < .01) 25 to 50% increase. The effect of SC-41930 on DTH expression was inhibited by a 10-fmol dose of LTB4. LTD4 receptor antagonist LY-171883 had no effect on DTH expression. Lipoxin A4 (LXA4) interferes with binding of LTB4 to T lymphocytes or neutrophils by reducing LTB4 receptor density. It caused a small but significant enhancement of DTH expression at 1-nmol doses when injected with PPD. Lipoxin B4 had no effect. Enhancement or inhibition of grossly visible delayed skin responses to PPD by LTB4. LTB4 receptor antagonists or LXA4 was not associated with qualitative or quantitative changes in superficial or deep dermal mononuclear cell infiltrates at the reaction site. We conclude that LTB4 modulates visible expression of DTH in vivo by a receptor-mediated mechanism.

A one year audit of fine needle aspiration cytology for the pre-operative diagnosis of breast disease.

In 1988, 985 patients presenting with breast disease, most with a palpable abnormality, were investigated by the triple approach (clinical examination, imaging and fine needle aspiration cytology [FNAC]). Using FNAC, 28% of patients were diagnosed as having carcinoma, 45% benign disease, 4% had suspicious cytology and 3% equivocal cytology. The remaining 20% had inadequate aspirates. Two false positive diagnoses of carcinoma were made (a false positive rate of 0.7%); one was a case of high grade non-Hodgkin's lymphoma and the other a papillary lesion with epithelial atypia. The false negative rate was 6.4%. Of these 49 patients, six had carcinoma-in-situ and 19 had low grade tumours. The absolute and complete sensitivities for the diagnosis of carcinoma in this series were 84.7% and 91.9% respectively and the absolute and complete specificities 99.7% and 98.3%, respectively. These figures compare favourably with those from other centres and confirm the efficacy of FNAC as part of the triple approach to the diagnosis of breast disease. The use of FNAC has resulted in a reduction in the number of Trucut and frozen section biopsies performed. Eighty three per cent of the patients with benign disease diagnosed by the triple approach have avoided excision biopsy, none of whom have subsequently been found to have carcinoma. Eighty patients with advanced breast carcinoma were spared operative intervention.