唐氏综合症（DS、21 三体、T21）患者发生短暂性骨髓生成异常 (TAM) 和急性巨核细胞白血病 (ML-DS) 的风险增加。 TAM 和 ML-DS 都需要 GATA1 的产前体细胞突变，从而产生截短的亚型 GATA1。个体 21 号染色体 (HSA21) 基因与 GATA1 协同作用进行白血病转化的机制很难研究，部分原因是野生型 GATA1 或 GATA1 的人类细胞模型有限。 HSA21 编码的 DYRK1A 在 ML-DS 中过度表达，可能是治疗靶点。为了确定 DYRK1A 如何与 GATA1 协同影响造血功能，我们使用基因编辑来破坏有或没有 GATA1 突变的同基因 T21 诱导多能干细胞 (iPSC) 中 DYRK1A 的所有 3 个等位基因。出乎意料的是，造血分化揭示了 DYRK1A 缺失与 GATA1 结合导致巨核细胞增殖增加和成熟减少。这种增殖表型与 D 型细胞周期蛋白的上调和 Rb 的过度磷酸化相关，从而允许 E2F 释放并解除其下游靶标的抑制。值得注意的是，DYRK1A 缺失对 T21/wtGATA1 巨核细胞没有影响。这些令人惊讶的结果表明，DYRK1A 和 GATA1 可能协同抑制 21 三体中的巨核细胞增殖，并且 DYRK1A 抑制可能不是 GATA1 相关白血病的治疗选择。

Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and de-repression of its downstream targets. Notably, DYRK1A loss had no effect in T21/wtGATA1 megakaryocytes. These surprising results suggest that DYRK1A and GATA1 may synergistically restrain megakaryocyte proliferation in Trisomy 21 and that DYRK1A inhibition may not be a therapeutic option for GATA1s-associated leukemias.