Normal and malignant megakaryopoiesis

Abstract

Megakaryopoiesis is the process by which bone marrow progenitor cells develop into mature megakaryocytes (MKs), which in turn produce platelets required for normal haemostasis. Over the past decade, molecular mechanisms that contribute to MK development and differentiation have begun to be elucidated. In this review, we provide an overview of megakaryopoiesis and summarise the latest developments in this field. Specially, we focus on polyploidisation, a unique form of the cell cycle that allows MKs to increase their DNA content, and the genes that regulate this process. In addition, because MKs have an important role in the pathogenesis of acute megakaryocytic leukaemia and a subset of myeloproliferative neoplasms, including essential thrombocythemia and primary myelofibrosis, we discuss the biology and genetics of these disorders. We anticipate that an increased understanding of normal MK differentiation will provide new insights into novel therapeutic approaches that will directly benefit patients.

Figure 1. Pathways to Megakaryocytes

A) The hematopoietic stem cell (HSC) gives rise to all blood cell lineages. In the classical model, the first lineage commitment step of HSCs results in a separation of common myeloid progenitors (CMP) and common lymphoid progenitors (CLP). The megakaryocyte erythroid progenitor (MEP), the precursor of megakaryocytes and erythroid cells, is derived from CMP. In the alternative model, the HSC directly gives rise to the MEP before restriction to myeloid or lymphoid lineages. B) Megakaryocyte progenitors, including the MEP, BFU-MK and CFU-MK, proliferate and differentiate into platelet-producing mature MKs. During this process, megakaryocytes undergo endomitosis to increase their size and DNA content. In murine cells, the DNA content can increase up to 128N. Simultaneously, expression of the megakaryocyte specific makers CD41 and CD42 is upregulated. LT-HSC, long-term HSC; ST-HSC, short-term HSC; Thy1, thymus 1 (“low” indicates low surface antigen and “−” indicates none detectable); Flt3, FMS-like tyrosine kinase 3; EPOR, erythropoietin receptor; CD41, glycoprotein IIb/IIIa or αIIbβ3 integrin receptor; G-CSFR, G-CSF receptor; MK, megakaryocyte; PLT, platelet; RBC, red blood cell; Mono, monocyte; Neutro, neutrophil; Baso, basophil; Eo, eosinophil; B, B cell; T, T cell; NK, nature killer cell; BFU-MK, burst forming unit-megakaryocyte; CFU-MK, colony forming unit-megakaryocyte.

Figure 2. The megakaryocyte lineage is abnormal in both ET and PMF

Bone marrow sections from a healthy individual (left), and patients with ET (middle) or PMF (right). Top, 20X, middle 40X original magnification. Note that ET megakaryocytes are typically larger than normal, increased in number, and contain chromatin that resembles leaves. In contrast, PMF megakaryocytes are small, dysplastic, and contain chromatin that resembles clouds. Images courtesy of Dr. Sandeep Gurbuxani (University of Chicago).