Acute myeloid leukemia (AML) is a rare type of cancer that affects the bone marrow and blood. This disease is due to mutations in certain genes and it has unknown etiology. Normally your bone marrow makes the exact number of blood cells and platelets that your body needs to function well. However in AML, the bone marrow makes abnormal myeloid cells referred to as myeloblasts. These cells don’t behave like normal blood cells since they multiply and don’t die off. This means there is less room for healthy blood cells, and as a result the bone marrow stops making new blood cells.
Bleeding is caused by disease- or treatment-related thrombocytopenia and complex systemic coagulopathies. Thrombocytopenia occurs when the bone marrow doesn’t make enough platelets, resulting in excess bleeding which may be difficult to stop. Acquired coagulation disorders are a common but complex complication in those with AML.
The aberrant expression of a transmembrane protein called tissue factor (TF) by these transformed myeloblasts (or pro-inflammatory monocytes) contributes to the procoagulant state. TF is the main initiator of the coagulation protease cascade. TF is constitutively expressed by many cancer cells as a result of activation or inactivation of oncogenes and tumor suppressor genes, respectively. The vast majority of TF is in a functionally inactive state but can be rapidly converted into its procoagulant isoform via different, synergistic mechanisms.
Procoagulant activity is regulated by an enzyme called protein disulfate isomerase (PDI) and its role in AML is unclear. Since PDI has been found in myeloblasts and is upregulated in several cancer types, authors investigated whether TF procoagulant function is regulated by thiol isomerases in AML. Several anti-cancer mechanisms are possible, namely inhibition of malignant cell growth, induction of cell cycle arrest and apoptosis and modulation of angiogenesis, inflammation, and oxidative stress. PDI is primarily expressed in the endoplasmic reticulum of eukaryotic cells, but it is also retained on cell surfaces or released into the vasculature upon endothelial or platelet activation.
Researchers in this study found that Bacitracin (sourced from TOKU-E), a pan-inhibitor of the PDI family, prevented lipopolysaccharide-induced monocyte TF production under inflammatory conditions and showed promising anticoagulant activity.
In summary, inhibition of PDI may thus be a promising therapeutic approach in the management of AML-associated coagulation disorders.
Reference
Beckmann L et al. Bacitracin and rutin regulate tissue factor production in inflammatory monocytes and Acute Myeloid Leukemia blasts. Cancers, 13(16), 3941. Link.