In:
Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 108, No. 8 ( 2023-02-16), p. 2130-2145
Abstract:
Sustained ANKRD26 expression associated with germline ANKRD26 mutations causes thrombocytopenia 2 (THC2), an inherited platelet disorder associated with a predisposition to leukemia. Some patients also present with erythrocytosis and/or leukocytosis. Using multiple human-relevant in vitro models (cell lines, primary patients’ cells and patient-derived induced pluripotent stem cells) we demonstrate for the first time that ANKRD26 is expressed during the early steps of erythroid, megakaryocyte and granulocyte differentiation, and is necessary for progenitor cell proliferation. As differentiation progresses, ANKRD26 expression is progressively silenced, to complete the cellular maturation of the three myeloid lineages. In primary cells, abnormal ANKRD26 expression in committed progenitors directly affects the proliferation/differentiation balance for the three cell types. We show that ANKRD26 interacts with and crucially modulates the activity of MPL, EPOR and G-CSFR, three homodimeric type I cytokine receptors that regulate blood cell production. Higher than normal levels of ANKRD26 prevent the receptor internalization that leads to increased signaling and cytokine hypersensitivity. These findings afford evidence how ANKRD26 overexpression or the absence of its silencing during differentiation is responsible for myeloid blood cell abnormalities in patients with THC2.
Type of Medium:
Online Resource
ISSN:
1592-8721
,
0390-6078
DOI:
10.3324/haematol.2022.282049
Language:
Unknown
Publisher:
Ferrata Storti Foundation (Haematologica)
Publication Date:
2023
detail.hit.zdb_id:
2186022-1
detail.hit.zdb_id:
2030158-3
detail.hit.zdb_id:
2805244-4
