Department of Pathology, Keck School of Medicine of University of Southern California, Los Angeles, CA 90033, USA.
Department of Pediatrics, Division of Hematology, Oncology, Blood and Marrow Transplantation, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
Int J Mol Sci. 2019 Jan 18;20(2):412. doi: 10.3390/ijms20020412.
Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stroma cells triggers intracellular signals regulating cell-adhesion-mediated drug resistance (CAM-DR). Stromal cell protection of ALL cells has been shown to require active AKT. In chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT pathway is reported. A novel FDA-approved PI3Kδ inhibitor, CAL-101/idelalisib, leads to downregulation of p-AKT and increased apoptosis of CLL cells. Recently, two additional PI3K inhibitors have received FDA approval. As the PI3K/AKT pathway is also implicated in adhesion-mediated survival of ALL cells, PI3K inhibitors have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K in normal hematopoietic cells, and in ALL. We focus on summarizing targeting strategies of PI3K in ALL.
急性淋巴细胞白血病 (ALL) 细胞与骨髓基质细胞的黏附会触发调节细胞黏附介导的药物耐药性 (CAM-DR) 的细胞内信号。已经表明，基质细胞对 ALL 细胞的保护需要 AKT 的活性。在慢性淋巴细胞白血病 (CLL) 中，已报道黏附介导的 PI3K/AKT 通路的激活。一种新型的美国食品和药物管理局批准的 PI3Kδ 抑制剂，CAL-101/idelalisib，导致 p-AKT 的下调和 CLL 细胞的凋亡增加。最近，另外两种 PI3K 抑制剂已获得美国食品和药物管理局的批准。由于 PI3K/AKT 通路也与 ALL 细胞黏附介导的存活有关，因此已在 ALL 中进行了 PI3K 抑制剂的临床前评估。然而，PI3K 抑制尚未被批准用于 ALL 的临床应用。在这里，我们回顾了 PI3K 在正常造血细胞和 ALL 中的作用。我们重点总结了 ALL 中 PI3K 的靶向策略。
