Megakaryopoiesis and Platelet Biology: Roles of Transcription Factors and Emerging Clinical Implications

Abstract

Platelets play a critical role in hemostasis and thrombus formation. Platelets are small, anucleate, and short-lived blood cells that are produced by the large, polyploid, and hematopoietic stem cell (HSC)-derived megakaryocytes in bone marrow. Approximately 3000 platelets are released from one megakaryocyte, and thus, it is important to understand the physiologically relevant mechanism of development of mature megakaryocytes. Many genes, including several key transcription factors, have been shown to be crucial for platelet biogenesis. Mutations in these genes can perturb megakaryopoiesis or thrombopoiesis, resulting in thrombocytopenia. Metabolic changes owing to inflammation, ageing, or diseases such as cancer, in which platelets play crucial roles in disease development, can also affect platelet biogenesis. In this review, I describe the characteristics of platelets and megakaryocytes in terms of their differentiation processes. The role of several critical transcription factors have been discussed to better understand the changes in platelet biogenesis that occur during disease or ageing.

Assessment of Platelet Mitochondrial Respiration in a Pediatric Population: A Pilot Study in Healthy Children and Children with Acute Lymphoblastic Leukemia

“…Furthermore, several transcription factors such as RUNX1, GATA1, FLI1, GFI1B, MECOM, ETV6, and NFE2 are implicated in megakaryopoiesis and platelet biogenesis. Both ETV6 and RUNX1 are known regulators of hematopoiesis [ 44 ]. In pediatric malignancies, the ETV6-RUNX1 (TEL-AML1) fusion gene is the most common chromosomal alteration, which occurs in approximately 25% of children with B cell precursor-acute lymphoblastic leukemia [ 45 ].…”

Vaccination Accelerates Liver-Intrinsic Expression of Megakaryocyte-Related Genes in Response to Blood-Stage Malaria

“…Etv6 encodes a transcriptional repressor belonging to the ETS family and is also known to be expressed in MEPs [20,57,58]. Remarkably, hepatic Etv6 expression in response to both malaria and vaccination was very similar to that of Stat3, though the constitutive expression of Etv6 in the liver was only about 1/3 of that of Stat3, with approximately 58 above normalization level (Figure 4).…”

“…TPO signaling through MPL requires the tyrosine kinase Janus kinase 2 (JA several other downstream signaling pathways including those mediated by sign ducers and activators of transcription (STAT)3 and STAT5 [20,57]. The time course of Mpl expression in response to blood-stage malaria totally differed from that of Thpo both in vaccination-protected and unprotected mice.…”

“…TPO signaling through MPL requires the tyrosine kinase Janus kinase 2 (JAK2) and several other downstream signaling pathways including those mediated by signal transducers and activators of transcription (STAT)3 and STAT5 [20,57]. Figure 4 shows the expression courses of Stat3 and Stat5b in the liver in response to blood-stage malaria.…”

“…was lower than that of Stat3, and its time course of expression inversely progressed to that of Stat3 in response to both malaria and vaccination. Among the transcription factors known to be involved at different stages of megakaryopoiesis in the bone marrow [20,57], there are ETV6 (ETS, erythroblast transformation specific, variant 6), GATA2 (Gata binding protein 2), NF-E2 (nuclear factor, erythroid 2), FLI1 (friend leukemia integration 1 transcription factor), ZFPM1 (Zinc finger protein, multitype 1; FOG1), RUNX1 (runt-related transcription factor), and MYB (myeloblastosis oncogene). In the liver, the genes encoding these transcription factors were constitutively expressed at different levels on day 0 p.i., and they were differently responsive to both malaria and protective vaccination (Figure 4).…”