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Pediatric Oncology
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Stephen Lowis, Rachel Cox, John Moppett, Helen Rees
In addition there is a unique condition called transient myeloid leukemia of Down syndrome (TMLDS) that occurs in at least 10% of neonates with DS. This condition is characterized by an abnormal clonal proliferation of megakaryoblasts that resembles AML but spontaneously resolves. Some 30–40% of such patients will go on to develop megakaryoblastic AML within the next 3 years. Of note, mutations in the GATA-1 gene on the X chromosome (encoding for a transcription factor essential for normal erythroid and megakaryoblastic differentiation) are found exclusively in TAM and DS-AML M7. Such mutations have subsequently been discovered in blood samples from Guthrie cards of patients with M7 and their identical twins, making it highly likely that they are an example of the so-called “first hit” in the process of leukemogenesis.
Congenital Amegakaryocytic Thrombocytopenia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
During thrombopoiesis, a pluripotent hematopoietic stem cell divides and forms myeloid stem cell which makes early commitment to megakaryoblast. After undergoing further division, megakaryoblast becomes immature megakaryocyte which completes its terminal differentiation into mature megakaryocytes and finally platelet that possesses many polyploid nuclei, extensive intracellular organelles (for platelet function), and membrane structures (for platelet shedding) [2,3].
Acute Leukemia and Myelodysplastic Syndromes
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Mark D. Brissette, James D. Cotelingam
Definitive identification of megakaryoblasts requires EM or immunophenotyping (Table 7). Platelet peroxidase activity is detected by EM and is probably the most sensitive and specific test for megakaryoblastic differentiation. In megakaryoblasts, peroxidase is localized to the nuclear membrane and endoplasmic reticulum as opposed to myeloblasts, where peroxidase activity occurs in cytoplasmic granules and the Golgi area.
Changes in megakaryopoiesis over ontogeny and their implications in health and disease
Published in Platelets, 2020
Patricia Davenport, Zhi-Jian Liu, Martha Sola-Visner
DS-TMD is a disorder characterized by increased proliferation and maturational arrest of erythromegakaryocytic cells, which resolves spontaneously within the first few months of life (thus the name Transient Myeloproliferative Disorder) [66]. TMD affects 5–10% of newborns with DS and is diagnosed by the presence of circulating megakaryoblasts, thrombocytopenia, and variable leukocytosis and anemia in the first days after birth (with all cases presenting within the first 2 months of life) [67]. The abnormality in megakaryopoiesis is thought to originate in the fetal liver, as suggested by its spontaneous resolution within months of birth (as hematopoiesis in the fetal liver ceases) and by the progressive megakaryoblast infiltration of hepatocytes with relative sparing of the BM [68]. Two cytogenetic changes, or “hits” occur prenatally that are thought to give rise to this condition. The first is the presence of Trisomy 21, which by itself is associated with increased frequency and clonogenicity of MK-erythroid progenitors in the fetal liver [69], and the second is a mutation in GATA-1, resulting in the exclusive production of the short isoform of GATA-1, termed GATA-1 short (GATA-1s) [70]. This isoform is 40 kDa in size, compared with the 47-kDa full-length protein, and is produced by the initiation of translation of the GATA-1 transcript at amino acid 84. Multiple mutations in the GATA1 gene have been described in patients with TMD, all of which reside within exon 2 of GATA-1 and result in the exclusive production of GATA-1s, which lacks the N-terminal transactivation domain.
Apoptosis is one cause of thrombocytopenia in patients with high-altitude polycythemia
Published in Platelets, 2023
Zhuoya Wang, Noryung Tenzing, Qiying Xu, Huifang Liu, Yi Ye, Yi Wen, Tana Wuren, Sen Cui
Bone marrow smear by bone marrow aspirate were collected from patients with HAPC (HAPC group; n = 55) and from patients with leukemia who had achieved complete remission more than 2 years after chemotherapy and whose bone marrow smears were taken more than 3 months after the last chemotherapy (control group; n = 25). All participants were hospitalized in Qinghai University Affiliated Hospital from 1 January 2017, to 31 May 2021, and came from high-altitude areas (2,500–4,500 m). All megakaryocytes (MKs) were counted on films from a 1.5 × 3.0-cm bone marrow smear stained with Wright’s stain and classified as megakaryoblast (stage I), promegakaryocyte (stage II), granular MK (stage III), or mature MK (stage IV) [16].
Unifying heterogeneous expression data to predict targets for CAR-T cell therapy
Published in OncoImmunology, 2021
Patrick Schreiner, Mireya Paulina Velasquez, Stephen Gottschalk, Jinghui Zhang, Yiping Fan
Pediatric acute myeloid leukemia (AML) is a challenging disease associated with high relapse and mortality rates.1–3The reported overall survival (OS) of children with AML is 65%–70%, which lags behind that for pediatric acute lymphoblastic leukemia (ALL).4 In recent years, improvement in outcomes of patients with AML has been largely attributed to a reduction in treatment-related mortality (TRM). Intensive chemotherapy regimens have resulted in increased TRM, leading to decreased OS. Also, patients with certain AML subtypes, such as megakaryoblastic AML (AMKL), carry an inherently poor prognosis.5 Thus, there is an urgent need to develop novel targeted therapies for pediatric AMKL.