Different murine knockout models recapitulating the development of T-ALL have demonstrated that PTEN abnormalities are at the hub of an intricate oncogenic network sustaining and driving leukemia development by activating several signaling cascades associated with drug-resistance and poor outcome.
Herein, we will review the function of PTEN in regulating hematopoiesis and leukemogenesis and discuss potential therapeutic approaches against leukemia with <i>PTEN</i> mutations.
Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways.
In three cases, multiplex qPCR and phylogenetic analysis were used to produce branching evolutionary trees recapitulating the snapshot history of T-ALL evolution in this leukaemia subtype, which confirmed that mutations in key T-ALL drivers, including NOTCH1 and PTEN, were subclonal and reiterative in distinct subclones.
Finally, We demonstrate that the absence of EGR1 expression dynamics in response to GM-CSF stimulation is one of the mechanisms underlying drug resistance to MAPK inhibitors in leukemia cells with PTEN deficiency.
Our study reveals a novel role for RhoA/ROCK1/PTEN/PI3K/Akt signaling in the regulation of mitochondrial translocation of cofilin and apoptosis and suggests MC-3129 as a potential drug for the treatment of human leukemia.
These studies provide the first direct evidence for both the involvement of the FGFR1 V561M mutation and PTEN inactivation in the development of resistance in leukemias overexpressing chimeric FGFR1.
In addition, depletion of β-Arrestin1 significantly decreased DNMT1 activity and PTEN methylation, and consistently increased PTEN expression in leukemia initiating cells-enriched fraction.
In vivo, the tumor growth inhibition caused by AT-101 was also associated with RhoA/ROCK1/PTEN activation and Akt inactivation in a mouse leukemia xenograft model.
Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells.
Primary and secondary xenotransplantation of TAL1-rearranged leukemia allowed development of leukemic subclones with newly acquired PTEN microdeletions.
Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN-loss-driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models.
Suppression of phosphatase and a tensin homolog deleted on chromosome 10 (PTEN) gene expression leading to activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway has been observed in many cancers including leukemia, making the PTEN gene and PI3K/Akt pathway a central target for cancer therapy.
These results demonstrate a critical role of PTEN in BCR-ABL-induced leukemias and suggest a potential strategy for the treatment of Philadelphia chromosome-positive leukemia.
Recent studies have demonstrated the critical role of the tumor suppressor PTEN/PI3 kinase pathway in regulating TIC in leukemia, brain, and intestinal tissues.
A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells.
To evaluate the role of the PTEN/MMAC1 gene in leukemia, bone marrow and/or peripheral blood from 62 acute myeloid leukemia (AML) patients, 5 hemopoietic cell lines (HL60, U937, Raji, KG-1, K562), and 30 normal controls were analyzed.
In this report, we demonstrate that cellular protein tyrosine phosphatase (PTPase) activity (especially in cytosol) in monoblastoid leukemia U937 cells increased up to 2-fold during the course of monocytic differentiation.