Bäumer Nicole, Bäumer Sebastian, Berkenfeld Frank, Stehling Martin, Köhler Gabriele, Berdel Wolfgang E, Müller-Tidow Carsten, Tschanter Petra
Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany; Interdisciplinary Center for Clinical Research (IZKF), University of Muenster, 48129 Muenster, Germany.
Department of Medicine A, Hematology/Oncology, University of Muenster, 48129 Muenster, Germany.
PLoS One. 2014 Dec 19;9(12):e115578. doi: 10.1371/journal.pone.0115578. eCollection 2014.
Functional differences between healthy progenitor and cancer initiating cells may provide unique opportunities for targeted therapy approaches. Hematopoietic stem cells are tightly controlled by a network of CDK inhibitors that govern proliferation and prevent stem cell exhaustion. Loss of Inca1 led to an increased number of short-term hematopoietic stem cells in older mice, but Inca1 seems largely dispensable for normal hematopoiesis. On the other hand, Inca1-deficiency enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion. Moreover, AML1-ETO9a-induced proliferation was not sustained in Inca1-deficient cells in vivo. As a consequence, leukemia induction and leukemia maintenance were severely impaired in Inca1-/- bone marrow cells. The re-initiation of leukemia was also significantly inhibited in absence of Inca1-/- in MLL-AF9- and c-myc/BCL2-positive leukemia mouse models. These findings indicate distinct functional properties of Inca1 in normal hematopoietic cells compared to leukemia initiating cells. Such functional differences might be used to design specific therapy approaches in leukemia.
健康祖细胞与癌症起始细胞之间的功能差异可能为靶向治疗方法提供独特的机会。造血干细胞受到一组CDK抑制剂网络的严格控制，该网络调控细胞增殖并防止干细胞耗竭。Inca1的缺失导致老年小鼠中短期造血干细胞数量增加，但Inca1对于正常造血似乎在很大程度上是可有可无的。另一方面，Inca1缺陷在细胞毒性应激时增强细胞周期进程并加速骨髓耗竭。此外，AML1-ETO9a诱导的增殖在体内Inca1缺陷细胞中无法持续。因此，Inca1基因敲除的骨髓细胞中白血病诱导和白血病维持严重受损。在MLL-AF9和c-myc/BCL2阳性白血病小鼠模型中，Inca1基因敲除时白血病的重新启动也受到显著抑制。这些发现表明，与白血病起始细胞相比，Inca1在正常造血细胞中具有不同的功能特性。这种功能差异可能用于设计白血病的特异性治疗方法。
