Platelets are highly dynamic, multifunctional “cell fragments” that are essential for hemostasis and play key roles in innate immunity, inflammation, maintenance of vascular integrity, carcinogenesis, and metastasis. Platelet content alters during their peripheral circulation, as they release content from storage granules and absorb molecules via receptor-mediated uptake as well as nonspecific internalization via membrane conduits — the surface canalicular system. Recent studies have highlighted a role for platelets in the early detection or “liquid biopsy” of cancers,1,2 with seminal work from the Wurdinger group demonstrating that specific alterations in the platelet transcriptome occur in patients with carcinomas, due to altered mRNA splicing of endogenous platelet RNA derived from parent megakaryocytes as well as sequestration of RNAs released by tumor cells, resulting in cancer-specific platelet transcriptome “signatures”.3
Could subtle changes to platelets be used for early identification of hematologic malignancies? Such a question is relevant given the growing understanding of clonal hematopoiesis and closer surveillance of patients at risk of therapy-associated leukemias. The study by Dr. Rui Wang and colleagues4 applied electron cryotomography (Cryo-ET) to determine whether changes in platelet architecture and organelle content may portend the development of leukemia in a mouse model of acute myeloid leukemia (AML) driven by the MLL-AF9 translocation. Traditional studies of platelet structural biology use transmission electron microscopy, where a beam of electrons is transmitted through a specimen to create an image with a magnification of 10,000×, substantially higher than can be achieved using a standard optical microscope. Transmission electron microscopy imaging requires samples to be fixed and dehydrated, which can cause artefactual changes in internal structure and architecture of organelles and macromolecules. In contrast, Cryo-ET immobilizes samples by vitrification using extremely rapid freezing, reducing dehydration artefacts, and capturing cells in a “snapshot” where dynamic and/or transient interactions and protein complexes are maintained.
Previous work by this group showed that subcellular features of platelets could discriminate between patients with benign adnexal masses and ovarian cancer, with qualitative differences in microtubule structure and increased number and area of mitochondria within platelets in cancer patients.4 In their recent study, Dr. Muyuan Chen and colleagues applied Cryo-ET and machine learning annotation algorithms5 to study platelet subcellular architecture over the course of AML development following irradiation and transplantation of mice with MLL-AF9 versus wild-type bone marrow.
In unirradiated, non-transplanted mice, the authors were able to visualize a smooth surface membrane with open canalicular system and ample mitochondria, and to distinguish glycogen particles, α and dense granules, and cytoplasmic microfilaments. In contrast to healthy mice, platelets from mice with frank AML were very small in size and almost completely devoid of granules.
Mice sampled prior to AML development had comparable blood counts to those transplanted with healthy bone marrow, and no difference in platelet size, area and number of granules, and number of mitochondria. However, around a quarter of the platelets studied had clearly abnormal mitochondrial structure, with increased circularity and a perimeter of empty spherical vesicles. They also found that platelets from mice with pre-AML showed a reduction in ATP production and down-regulation of the oxidative phosphorylation pathway, in keeping with mitochondrial dysfunction.
Mitochondria in platelets provide energy for platelet activation, aggregation, secretion, and apoptosis. Therefore, depletion or degradation of mitochondrial function may contribute to platelet dysfunction and bruising or bleeding in AML. Remarkably, it was also recently reported that platelets donate metabolically-competent mitochondria to other cell types such as mesenchymal stromal cells, thereby enhancing their angiogenic activity and promoting tissue repair.6 Mitochondrial dysfunction may therefore significantly alter platelet function and communication.
This study suggests that changes to the structure and function of platelet mitochondria may be an early feature of leukemogenesis and may contribute to platelet dysfunction in hematologic malignancies. Further studies are required to determine the biological significance of these observations and whether the study of mitochondrial content or metabolic activity of platelets is feasible in a clinical diagnostic pathway. Additionally, the impact of changes to intercellular mitochondrial transfer from platelets to other cell types in cancer initiation and propagation may be an interesting avenue for further research.
Dr. Psaila indicated no relevant conflicts of interest.