The role of tumor suppressor p15Ink4b in the regulation of hematopoietic progenitor cell fate.

Epigenetic silencing of the tumor suppressor gene p15Ink4b (CDKN2B) is a frequent event in blood disorders like acute myeloid leukemia and myelodysplastic syndromes. The molecular function of p15Ink4b in hematopoietic differentiation still remains to be elucidated. Our previous study demonstrated that loss of p15Ink4b in mice results in skewing of the differentiation pattern of the common myeloid progenitor towards the myeloid lineage. Here, we investigated a function of p15Ink4b tumor suppressor gene in driving erythroid lineage commitment in hematopoietic progenitors. It was found that p15Ink4b is expressed more highly in committed megakaryocyte–erythroid progenitors than granulocyte–macrophage progenitors. More importantly, mice lacking p15Ink4b have lower numbers of primitive red cell progenitors and a severely impaired response to 5-fluorouracil- and phenylhydrazine-induced hematopoietic stress. Introduction of p15Ink4b into multipotential progenitors produced changes at the molecular level, including activation of mitogen-activated protein kinase\extracellular signal-regulated kinase (MEK/ERK) signaling, increase GATA-1, erythropoietin receptor (EpoR) and decrease Pu1, GATA-2 expression. These changes rendered cells more permissive to erythroid commitment and less permissive to myeloid commitment, as demonstrated by an increase in early burst-forming unit-erythroid formation with concomitant decrease in myeloid colonies. Our results indicate that p15Ink4b functions in hematopoiesis, by maintaining proper lineage commitment of progenitors and assisting in rapid red blood cells replenishment following stress.

肿瘤抑制基因p15Ink4b（CDKN2B）的表观遗传沉默在急性髓系白血病和骨髓增生异常综合征等血液疾病中是常见事件。p15Ink4b在造血分化中的分子功能仍有待阐明。我们之前的研究表明，小鼠中p15Ink4b的缺失导致共同髓系祖细胞的分化模式向髓系谱系偏移。在此，我们研究了p15Ink4b肿瘤抑制基因在驱动造血祖细胞向红系谱系分化中的作用。研究发现，p15Ink4b在定向的巨核细胞 - 红细胞祖细胞中的表达高于粒细胞 - 巨噬细胞祖细胞。更重要的是，缺乏p15Ink4b的小鼠原始红细胞祖细胞数量较少，并且对5 - 氟尿嘧啶和苯肼诱导的造血应激反应严重受损。将p15Ink4b导入多能祖细胞会在分子水平上产生变化，包括丝裂原活化蛋白激酶/细胞外信号调节激酶（MEK/ERK）信号通路的激活，GATA - 1、促红细胞生成素受体（EpoR）增加以及Pu1、GATA - 2表达降低。这些变化使细胞更易于向红系分化，而不易向髓系分化，这表现为早期爆式集落形成单位 - 红系形成增加，同时髓系集落减少。我们的研究结果表明，p15Ink4b在造血过程中发挥作用，通过维持祖细胞正确的谱系分化，并在应激后协助快速补充红细胞。