Signal transduction defects in canine cyclic hematopoiesis

Canine Cyclic Hematopoiesis (CH) is an autosomal recessive disease of collie dogs, which is characterized by partial albinism and cyclic hematopoiesis at 14 day intervals. Previous studies on canine CH platelets have shown defective aggregation patterns to several agonists as well as a storage pool defects with decreased stores of dense granule nucleotides and serotonin. Recent studies have also identified defective phosphorylation of a 40kD protein which is the substrate for protein kinase C in platelets.

To further investigate the basis of phosphoinositide signal transduction defects in dogs with cyclic hematopoiesis, I compared platelet and neutrophil function in normal and CH dogs treated with recombinant human granulocyte colony stimulating factor (rhG-CSF). RhG-CSF eliminated neutrophil cycles associated with CH and eliminated endogenous G-CSF cycles in one CH dog and partially eliminated G-CSF cycles in another CH dog. However treatment with rhG-CSF failed to eliminate decreased platelet granule stores of serotonin or decreased neutrophil granule stores of myeloperoxidase (MPO). Moreover, defective thrombin, collagen and IV platelet activating factor (PAF)-stimulated platelet aggregation and defective serotonin secretion persisted despite correction of the cell cycling in the CH dogs.

Superoxide production of CH dog neutrophils to three doses of phorbol myristate acetate (PMA) showed decreases relative to control dogs. Similar to the platelet storage pool defect, the MPO granule stores in CH dogs were also found to be decreased. However, CH neutrophils showed normal chemotaxis to three doses of PAF. In addition, when neutrophils were preincubated with cholera or pertussis toxin there were no significant differences in inhibition of PAF stimulated chemotaxis in the two groups of dogs.

The identification of similar defects in storage pools and signal transduction in platelets and neutrophils from CH dogs indicates a connection between storage pool function and the signal transduction cascade which may be involved in the pathophysiology of CH.