Targeting PI3K Signaling in Acute Lymphoblastic Leukemia

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.

Phosphoinositide-Dependent Signaling in Cancer: A Focus on Phospholipase C Isozymes

“…Notably, they reduce cell proliferation in these cancer types [81]. CAL-101 or idelalisib which is an approved PI3K inhibitor induces elevated cell death in chronic lymphocytic leukemia [82]. Interestingly, alterations in both PLCβ1 and PI3K/Akt/mTOR pathways have been associated with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [57,83,84].…”

Integration of immunome with disease-gene network reveals common cellular mechanisms between IMIDs and drug repurposing strategies

“…The pathway enrichment ( Supplementary Figure 4B ) of these genes revealed pathways associated to TCR and BCR signaling and PI3K/AKT signaling. Interestingly, these pathways have been shown to be important for survival of cancer cells and are targets for anti-cancer drugs in acute and chronic lymphoid leukemia 32 . Thus the DIME network of lymphoid leukemia revealed the key DAGs and DACs implicated in the disease.…”

Pathogenesis of pediatric B‑cell acute lymphoblastic leukemia: Molecular pathways and disease treatments (Review)

“…The PI3K/Akt signaling pathway is activated in various types of liquid tumors such as B cell precursor-ALL (36) and hence it serves an important role in pathogenesis (37). In the leukemia microenvironment, marrow stromal cells (MSCs) promote the proliferation of leukemic cells and strengthen their resistance to chemotherapy, through PI3K/Akt signaling pathway (38). MSCs secrete C-X-C motif chemokine 12 that acts on C-X-C chemokine receptor type 4 of the leukemia blast cells and through the PI3K and Wnt pathways exert influences on their survival and proliferation (39).…”