| Autor: |
Chiu, Sung K., Orive, Stephanie L., Moon, Mitchell J., Saw, Jesslyn, Ellis, Sarah, Kile, Benjamin T., Huang, Yizhou, Chacon, Diego, Pimanda, John E., Beck, Dominik, Hamilton, Justin R., Tremblay, Cedric S., Curtis, David J. |
| Zdroj: |
Blood; September 2019, Vol. 134 Issue: 10 p826-835, 10p |
| Abstrakt: |
The stem cell leukemia (Scl or Tal1) protein forms part of a multimeric transcription factor complex required for normal megakaryopoiesis. However, unlike other members of this complex such as Gata1, Fli1, and Runx1, mutations of Sclhave not been observed as a cause of inherited thrombocytopenia. We postulated that functional redundancy with its closely related family member, lymphoblastic leukemia 1 (Lyl1) might explain this observation. To determine whether Lyl1 can substitute for Scl in megakaryopoiesis, we examined the platelet phenotype of mice lacking 1 or both factors in megakaryocytes. Conditional Sclknockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 (Pf4) promoter generated megakaryocytes with markedly reduced but not absent Scl. These Pf4Sclc-KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, Pf4Sclc-KO mice generated on an Lyl1-null background (double knockout [DKO] mice) had severe macrothrombocytopenia, abnormal megakaryocyte morphology, defective pro-platelet formation, and markedly impaired platelet aggregation. DKO megakaryocytes, but not single-knockout megakaryocytes, had reduced expression of Gata1, Fli1, Nfe2, and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared Scland Lyl1 E-boxbinding sites that were also enriched for Gata1, Ets, and Runx1motifs. Thus, Scl and Lyl1 share functional roles in platelet production by regulating expression of partner proteins including Gata1. We propose that this functional redundancy provides one explanation for the absence of Scland Lyl1mutations in inherited thrombocytopenia. |
| Databáze: |
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