ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis

Haematologica. 2023 Feb 16. doi: 10.3324/haematol.2022.282049. Online ahead of print.ABSTRACTSustained ANKRD26 expression associated with germline ANKRD26 mutations causes Thrombocytopenia 2 (THC2), an inherited platelet disorder associated with leukemia predisposition. Some patients also present with erythrocytosis and/or leukocytosis. Using multiple human-relevant in vitro models (cell lines, primary patient cells and patient-derived iPSCs) 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 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 impacts 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 an ANKRD26 overexpression or the absence of its silencing during differentiation is responsible of myeloid blood cell abnormalities in TCH2 patients.PMID:36794499 | DOI:10.3324/haematol.2022.282049

Source: Haematologica - February 16, 2023 Category: Hematology Authors: Francesca Basso-Valentina Alessandro Donada Vladimir T Manchev Manuel Lisetto Nathalie Balayn Jean Edouard Martin Delphine Muller Cecilia Paola Marin Oyarzun H élène Duparc Brahim Arkoun Alessandro Cumin Lionel Faivre Nathalie Droin Ida Biunno Alessandr Source Type: research