Abstract
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.
Highlights
Chemotherapeutic resistance in adults with acute lymphoblastic leukemia (ALL) remains a major problem [1]
The bone marrow environment has been shown to promote cell adhesion-mediated drug resistance (CAM-DR) in leukemia cells, which may contribute to relapse
Supportive of this finding are the results of Eldfors et al indicating that idelalisib is effective against TCF3-PBX1 B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL)
Summary
Chemotherapeutic resistance in adults with acute lymphoblastic leukemia (ALL) remains a major problem [1]. The bone marrow environment has been shown to promote cell adhesion-mediated drug resistance (CAM-DR) in leukemia cells, which may contribute to relapse. The bone marrow (BM) is the most frequent site of relapse in ALL [3,4], and BM relapse is associated with a worse prognosis than isolated extramedullary relapse [3,5] These findings point to a protective role of the BM as a safe haven for drug-resistant ALL cells. In vitro studies show that contact between leukemia and stromal cells promotes cell adhesion-mediated drug resistance (CAM-DR) [6,7], which prevents apoptosis of ALL cells [8,9,10].
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