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• W4313184564 abstract "Germline ANKRD26 mutations cause autosomal dominant thrombocytopenia with MDS/leukemia predisposition (ANKRD26-RT). ANKRD26 is highly expressed in hematopoietic stem (HSCs)/progenitor cells, but is silenced during megakaryocyte (Mk) maturation. Mutations in ANKRD26-RT cluster within a transcriptional silencer region and cause a failure to fully repress ANKRD26 during terminal megakaryopoiesis. Yet the normal function of ANKRD26 and the mechanism(s) by which dysregulated ANKRD26 expression cause thrombocytopenia and leukemia predisposition remain poorly understood. We have generated a mouse overexpression model of ANKRD26-RT by inserting the human ANKRD26 cDNA, preceded by a transcriptional stopper cassette flanked by loxP sites, into the Rosa26 locus. Activation within HSCs (Mx1-Cre) or Mks (PF4-Cre) leads to thrombocytopenia and small Mks with hypolobulated nuclei, similar to what is observed in ANKRD26-RT patients. ANKRD26 was recently reported to be a centriole component and to activate the PIDDosome complex when cells become aneuploid, leading to cell cycle arrest and/or apoptosis. We hypothesize that ANKRD26 silencing is necessary for mature Mks to avoid triggering the aneuploidy checkpoint as they undergo polyploidization. This is being tested in our mouse model and human systems. ANKRD26 has also been shown to be phosphorylated by ATM/ATR following cell radiation. We found that ANKRD26 over expression causes a failure of cell cycle arrest, delayed clearance of g-H2AX nuclear foci, and impaired p21 up regulation following irradiation. We also find that primary CD34+ bone marrow cells from ANKRD26-RT patients contain increased g-H2AX foci compare to healthy controls. We propose a model in which dysregulated ANKRD26 expression alters the stoichiometry of DNA damage response complexes leading to MDS/leukemia predisposition. Germline ANKRD26 mutations cause autosomal dominant thrombocytopenia with MDS/leukemia predisposition (ANKRD26-RT). ANKRD26 is highly expressed in hematopoietic stem (HSCs)/progenitor cells, but is silenced during megakaryocyte (Mk) maturation. Mutations in ANKRD26-RT cluster within a transcriptional silencer region and cause a failure to fully repress ANKRD26 during terminal megakaryopoiesis. Yet the normal function of ANKRD26 and the mechanism(s) by which dysregulated ANKRD26 expression cause thrombocytopenia and leukemia predisposition remain poorly understood. We have generated a mouse overexpression model of ANKRD26-RT by inserting the human ANKRD26 cDNA, preceded by a transcriptional stopper cassette flanked by loxP sites, into the Rosa26 locus. Activation within HSCs (Mx1-Cre) or Mks (PF4-Cre) leads to thrombocytopenia and small Mks with hypolobulated nuclei, similar to what is observed in ANKRD26-RT patients. ANKRD26 was recently reported to be a centriole component and to activate the PIDDosome complex when cells become aneuploid, leading to cell cycle arrest and/or apoptosis. We hypothesize that ANKRD26 silencing is necessary for mature Mks to avoid triggering the aneuploidy checkpoint as they undergo polyploidization. This is being tested in our mouse model and human systems. ANKRD26 has also been shown to be phosphorylated by ATM/ATR following cell radiation. We found that ANKRD26 over expression causes a failure of cell cycle arrest, delayed clearance of g-H2AX nuclear foci, and impaired p21 up regulation following irradiation. We also find that primary CD34+ bone marrow cells from ANKRD26-RT patients contain increased g-H2AX foci compare to healthy controls. We propose a model in which dysregulated ANKRD26 expression alters the stoichiometry of DNA damage response complexes leading to MDS/leukemia predisposition." @default.
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• W4313184564 date "2022-01-01" @default.
• W4313184564 modified "2023-09-23" @default.
• W4313184564 title "2004 – GERMLINE ANKRD26 MUTATIONS IN FAMILIAL THROMBOCYTOPENIA AND LEUKEMIA PREDISPOSITION" @default.
• W4313184564 doi "https://doi.org/10.1016/j.exphem.2022.07.036" @default.
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