Tyrosine kinase inhibitors (TKIs) induce molecular remission in the majority of patients with chronic myelogenous leukemia (CML), but the persistence of CML stem cells hinders cure and necessitates indefinite TKI therapy. We report that CML stem cells upregulate the expression of pleiotrophin (PTN) and require cell-autonomous PTN signaling for CML pathogenesis in BCR/ABL⁺ mice. Constitutive PTN deletion substantially reduced the numbers of CML stem cells capable of initiating CML in vivo. Hematopoietic cell–specific deletion of PTN suppressed CML development in BCR/ABL⁺ mice, suggesting that cell-autonomous PTN signaling was necessary for CML disease evolution. Mechanistically, PTN promoted CML stem cell survival and TKI resistance via induction of Jun and the unfolded protein response. Human CML cells were also dependent on cell-autonomous PTN signaling, and anti-PTN antibody suppressed human CML colony formation and CML repopulation in vivo. Our results suggest that targeted inhibition of PTN has therapeutic potential to eradicate CML stem cells.

中文翻译：

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慢性粒细胞白血病干细胞需要细胞自主性的多营养因子信号传导

酪氨酸激酶抑制剂（TKIs）在大多数患有慢性粒细胞性白血病（CML）的患者中诱导分子缓解，但是CML干细胞的持续存在阻碍了治愈，因此需要无限期的TKI治疗。我们报告，CML干细胞上调多效性蛋白（PTN）的表达，并要求细胞自主PTN信号转导BCR / ABL ⁺小鼠CML发病机理。组成性PTN缺失大大减少了能够在体内启动CML的CML干细胞的数量。PTN的造血细胞特异性缺失抑制了BCR / ABL ⁺小鼠中CML的发展，这表明细胞自主PTN信号对于CML疾病的发展是必需的。从机制上讲，PTN通过诱导Jun促进CML干细胞存活和TKI抗性以及展开的蛋白质反应。人CML细胞还依赖于细胞自主PTN信号传导，并且抗PTN抗体在体内可抑制人CML集落形成和CML繁殖。我们的结果表明，对PTN的靶向抑制具有根除CML干细胞的治疗潜力。