1025 – EXPLORING THE MEGAVERSE—MEGAKARYOCYTES, PLATELETS AND MYELOPROLIFERATIVE NEOPLASMS

Abstract

Megakaryocytes are one of the largest and rarest cells in the human body—with a giant cell size and massive, polyploid nucleus. This confers a tremendous synthetic capacity—and a handful of megakaryocytes are able to release billions of tiny platelets into our bloodstream every day. Platelets, in contrast to their parent megakaryocytes, have no nucleus at all. Despite their lack of a nucleus, we recently discovered that platelets contain a repertoire of DNA fragments acquired during circulation by “hoovering up” cell-free DNA shed by nucleated cells—including cancer cell-derived and free fetal DNA. In our ongoing work, we are exploring how megakaryocytes tolerate the successive rounds of whole genome duplication and the implications of this for their genome stability.

Megakaryocytes, along with related cells, are major contributors to the disease features and progression of myeloproliferative neoplasms (MPNs)—chronic blood cancers occurring in around 4,000 people in the UK each year. We are interested in how megakaryocytes, MPN stem cells, and the bone marrow stroma interact to drive progression to advanced-stage MPN, in particular myelofibrosis, with an overarching goal of developing more disease-modifying treatments that improve outcomes for patients. To explore this, we have implemented novel experimental platforms, including human organoids. We are currently also using these to unpick the mechanisms that fuel progression and to develop ex vivo systems that evaluate emerging cancer cell-targeting therapies in more relevant human tumor microenvironments.

Megakaryocytes are one of the largest and rarest cells in the human body—with a giant cell size and massive, polyploid nucleus. This confers a tremendous synthetic capacity—and a handful of megakaryocytes are able to release billions of tiny platelets into our bloodstream every day. Platelets, in contrast to their parent megakaryocytes, have no nucleus at all. Despite their lack of a nucleus, we recently discovered that platelets contain a repertoire of DNA fragments acquired during circulation by “hoovering up” cell-free DNA shed by nucleated cells—including cancer cell-derived and free fetal DNA. In our ongoing work, we are exploring how megakaryocytes tolerate the successive rounds of whole genome duplication and the implications of this for their genome stability.

Megakaryocytes, along with related cells, are major contributors to the disease features and progression of myeloproliferative neoplasms (MPNs)—chronic blood cancers occurring in around 4,000 people in the UK each year. We are interested in how megakaryocytes, MPN stem cells, and the bone marrow stroma interact to drive progression to advanced-stage MPN, in particular myelofibrosis, with an overarching goal of developing more disease-modifying treatments that improve outcomes for patients. To explore this, we have implemented novel experimental platforms, including human organoids. We are currently also using these to unpick the mechanisms that fuel progression and to develop ex vivo systems that evaluate emerging cancer cell-targeting therapies in more relevant human tumor microenvironments.