Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Australia.
Department of Clinical Haematology, Alfred Health, Melbourne, Australia.
Blood. 2019 Sep 5;134(10):826-835. doi: 10.1182/blood.2019896175. Epub 2019 Jul 12.
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 have 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 knockout (KO) mice crossed with transgenic mice expressing Cre recombinase under the control of the mouse platelet factor 4 () promoter generated megakaryocytes with markedly reduced but not absent These -KO mice had mild thrombocytopenia and subtle defects in platelet aggregation. However, -KO mice generated on an -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 , , , and many other genes that cause inherited thrombocytopenia. These gene expression changes were significantly associated with shared and binding sites that were also enriched for , , and motifs. 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 and mutations in inherited thrombocytopenia.
干细胞白血病 (Scl 或 Tal1) 蛋白是一种多聚体转录因子复合物的一部分，该复合物是正常巨核细胞生成所必需的。然而，与该复合物的其他成员（如 Gata1、Fli1 和 Runx1）不同，尚未观察到 突变是遗传性血小板减少症的原因。我们推测，与其密切相关的家族成员淋巴母细胞白血病 1 (Lyl1) 的功能冗余可能解释了这一观察结果。为了确定 Lyl1 是否可以替代 Scl 在巨核细胞生成中发挥作用，我们检查了缺乏 1 或两者的巨核细胞中的血小板表型。用表达 Cre 重组酶的转基因小鼠与在血小板因子 4 () 启动子控制下表达 Cre 重组酶的小鼠进行杂交，生成了血小板显著减少但并非完全不存在的 -KO 小鼠。这些 -KO 小鼠有轻度血小板减少症和血小板聚集轻微缺陷。然而，在 -null 背景上生成的 -KO 小鼠（双重 KO [DKO] 小鼠）有严重的巨血小板减少症、异常的巨核细胞形态、前血小板形成缺陷和明显受损的血小板聚集。DKO 巨核细胞，而不是单敲除巨核细胞，下调了许多导致遗传性血小板减少症的基因，如 、 、 等。这些基因表达变化与共享的 和 结合位点显著相关，这些结合位点也富含 、 和 基序。因此，Scl 和 Lyl1 通过调节包括 Gata1 在内的伙伴蛋白的表达在血小板生成中发挥功能作用。我们提出，这种功能冗余是遗传性血小板减少症中缺失 和 突变的一个解释。
