Menell, JS and others
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 1, 2001
Reviewers: Kenneth Blank, MD
Source: The New England journal of Medicine April 1, 1999 Vol. 340 No 13 p994
Scientists and physicians discovered a method to take advantage of APL's unique biology when it was discovered that all-trans-retinoic acid (ATRA)causes APL cells to differentiate and stop rapidly dividing. Today, the treatment of APL differs from all other acute myeloid leukemias byincorporating ATRA in the induction and consolidation phases of treatment. The use of ATRA has significantly improved treatment results overconventional chemotherapy.
Another unique aspect of APL is its association with bleeding disorders. Patients with APL frequently have hemorrhagic events, which may besevere enough to lead to the patient's death. The reason for this syndrome is not clear. Some investigators believe it is caused by disseminatedintravascular coagulation (DIC), a syndrome in which clotting occurs throughout the body causing a depletion of clotting factors and subsequentbleeding. Another theory attributes the bleeding diathesis to rapid clot breakdown. Specifically, clots, which are formed largely by fibrin, are rapidlydissolved in APL patients because of an overproduction of the enzyme plasmin that cleaves fibrin. Support for the latter theory appears in a paperpublished in the April 1, 1999 New England Journal of Medicine.
The authors of the report hypothesized that plasmin production in APL is enhanced because APL cells express great quantities of a cell surfaceprotein called annexin II, a protein that activates plasmin. To test this theory the authors studied APL cells for annexin II quantities and correlated thiswith plasmin levels.
The role of annexin II in the production of plasmin was examined using advanced molecular techniques. For example, cells lacking the PML/RARtranslocation were transfected with a plasmid containing a full-length copy of the annexin II gene. Transfected cells were found to express annexin IItwice as effectively as un-transfected control cells, suggesting that the expression of annexin II directly correlates with the capacity of produceplasmin.
All-trans-retinoic acid significantly decreased the synthesis of annexin II. This finding related to both the cell surface expression of annexin II and themRNA levels of annexin II. Using nuclear run on analysis, the authors found that ATRA inhibition of annexin II expression is likely secondary to adecrease in the annexin II gene transcription, and not enhanced degradation of the protein.
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