Description:
Last few years have witnessed a tremendous advance in approaches to study the basic biology of megakaryocytes and platelets and their role in disease. This session focuses on three state-of-the-art approaches that have provided remarkable new insights. The first talk focuses on the application of single cell multi-omic approaches to advance understanding of megakaryocyte biology and their application to myelofibrosis, an acquired stem cell disorder. The second talk extends this with a focus on the unique insights provided by studies using induced pluripotent stem cell (iPSC) in the context of a disorder associated with germline mutations in hematopoietic transcription factor RUNX1. These patients are characterized by aberrations in platelet function and number and a predisposition to myeloid malignancies. These studies cover the spectrum from insights into the biology of the disease to potential therapeutic approaches. Last few years have seen an explosion of information on the gene abnormalities in patients with inherited platelet disorders, and much of this has come through the application of new-generation sequencing - the focus of the third talk. These approaches have advanced understanding of the genetic abnormalities in patients and provided novel and unexpected insights into the causative genes and their role in platelets and megakaryocytes.

Dr. Bethan Psaila will discuss the application of single cell multi-omic approaches to studying normal and aberrant pathways of megakaryocyte differentiation. She will discuss changes to megakaryopoiesis over normal human ontogeny and the mechanisms of megakaryocyte-biased hematopoiesis in myelofibrosis. Single cell approaches can identify heterogeneous megakaryocyte subpopulations with distinct metabolic and inflammatory signatures, and implications for novel approaches for therapeutic targeting of malignant megakaryocytes will be discussed.

Dr. Mortimer Poncz will address the role induced pluripotent stem cells (iPSC) have played in highlighting mechanisms in inherited platelet/megakaryocyte disorders. RUNX1 is a transcription factor central to hematopoiesis. Haploinsufficiency of RUNX1 results in a clinical disorder termed Familial Platelet Disorder associated with Myeloid Malignancy or FPDMM that is associated with quantitative and qualitative defects and an increased risk of myeloid leukemia. Studies of iPSCs derived from patients with FPDMM recapitulate the defect in megakaryopoiesis and have led to new insights into the pathogenesis of this disorder, including a deficiency of megakaryocyte-biased progenitor cells and upregulation of proinflammatory pathways during megakaryopoiesis. These pathogenic insights have also led to therapeutics that prevent the defect in megakaryopoiesis in iPSC and primary cell ex vivo studies.

Dr. Kathleen Freson will discuss the value of next generation sequencing (NGS) in providing new insights into platelet and megakaryocyte biology. Patient studies have significantly contributed to our current knowledge of platelet and megakaryocyte biology. NGS-based multi-gene panel tests comprising all platelet disorder genes known today can diagnose about 26 to 48% of patients with platelet function and formation disorders, respectively. This means that many disease-related genes are still unknown and often totally unexpected genes are discovered in exomes and genomes as candidate for a novel platelet disorder. Disease models, platelet transcriptomics and other functional assays are still critical to prove causality and understand their role in platelet and megakaryocyte biology.