Abstract
Thrombopoiesis following severe bone marrow injury frequently is delayed, thereby resulting in life-threatening thrombocytopenia for which there are limited treatment options. The reasons for these delays in recovery are not well understood. Protein kinase C (PKC) agonists promote megakaryocyte differentiation in leukemia cell lines and primary cells. However, little is known about the megakaryopoietic effects of PKC agonists on primary CD34+ cells grown in culture or in vivo. Here we present evidence that the novel PKC isoform-selective agonist 3,20 ingenol dibenzoate (IDB) potently stimulates early megakaryopoiesis of human CD34+ cells. In contrast, broad spectrum PKC agonists failed to do so. In vivo, a single intraperitoneal injection of IDB selectively increased platelets in mice without affecting hemoglobin or white counts. Finally, IDB strongly mitigated radiation-induced thrombocytopenia, even when administered 24 hours after irradiation. Our data demonstrate that novel PKC isoform agonists such as IDB may represent a unique therapeutic strategy for accelerating the recovery of platelet counts following severe marrow injury.
Highlights
Despite recent advances in our understanding of megakaryocyte growth and platelet production, thrombocytopenia remains a difficult problem in the clinical management of patients with hematologic malignancies
When CD34+ progenitors were cultured in TPO/stem cell factor (SCF), the early period of culture was characterized by proliferation with little terminal megakaryocytic differentiation, typically occurring in the first week in culture (Fig. 1A)
Since protein kinase C (PKC) agonists promote megakaryocytic differentiation of erythroleukemia cell lines, we investigated whether they might promote early megakaryocytic differentiation of normal human CD34+ cells
Summary
Despite recent advances in our understanding of megakaryocyte growth and platelet production, thrombocytopenia remains a difficult problem in the clinical management of patients with hematologic malignancies. There remains an important clinical need for the development of novel approaches to accelerate platelet recovery following myeloablative therapy or severe marrow injury It has been over 25 years since the original observations were reported describing the unique ability of protein kinase C (PKC) agonists to promote megakaryocytic differentiation of primary murine cells [8,9]. These early studies, which examined the effects of PKC agonists on megakaryocytic differentiation of normal hematopoietic progenitors, were carried out before megakaryocyte culture conditions from early CD34+ progenitors had been developed. Little is known about the megakaryopoietic effects of PKC agonists on primary CD34selected cells grown in well-defined culture conditions or in vivo
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