Genomic landscape of megakaryopoiesis and platelet function defects

Abstract

Megakaryopoiesis is a complex, stepwise process that takes place largely in the bone marrow. At the apex of the hierarchy, hematopoietic stem cells undergo a number of lineage commitment decisions that ultimately lead to the production of polyploid megakaryocytes. On average, megakaryocytes release 10(11) platelets per day into the blood that repair vascular injuries and prevent excessive bleeding. This differentiation process is tightly controlled by exogenous and endogenous factors, which have been the topics of intense research in the hematopoietic field. Indeed, a skewing of megakaryocyte commitment and differentiation may entail the onset of myeloproliferative neoplasms and other preleukemic disorders together with acute megakaryoblastic leukemia, whereas quantitative or qualitative defects in platelet production can lead to inherited platelet disorders. The recent advent of next-generation sequencing has prompted mapping of the genomic landscape of these conditions to provide an accurate view of the underlying lesions. The aims of this review are to introduce the physiological pathways of megakaryopoiesis and to present landmark studies on acquired and inherited disorders that target them. These studies have not only introduced a new era in the fields of molecular medicine and targeted therapies but may also provide us with a better understanding of the mechanisms underlying normal megakaryopoiesis and thrombopoiesis that can inform efforts to create alternative sources of megakaryocytes and platelets.

Figure 1

Main molecular mechanisms affected in malignant megakaryopoiesis and platelet function defects. Schematic representation of (A) TPO/MPL signaling pathway together with (B) the most relevant transcriptional regulators of megakaryocyte commitment, differentiation, and maturation. GP2B (CD41) is a component of the GPIIb-IIIa glycoprotein complex. GP9 (CD42a), GP1BA (CD42b), and GP1BB (CD42c) are components of the GPIb-IX-V glycoprotein complex. HSC, hematopoietic stem cell; MEP, megakaryocyte-erythroid progenitor; MK, megakaryocyte.

Figure 2

PMF, ET, RARS-T, and 5q- syndrome. The World Health Organization classification, the mutational landscape, and the distinctive clinical and morphologic features for the 4 malignant diseases are described. The schematic representation of megakaryocyte morphology, as a hallmark distinctive of PMF, ET, RARS-T, and 5q- syndrome, is shown at the bottom of the figure.

Figure 3

Schematic cartoon representing the proteins mutated in inherited platelet function disorders. Light blue ovoids represent α-granules, dark blue spheres represent δ-granules. LAD-III, leukocyte adhesion deficiency-III syndrome; VWD, von Willebrand disease.