Journal
LEUKEMIA
Volume 31, Issue 11, Pages 2355-2364Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2017.80
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Funding
- NIH/NCI [R01 CA164346, R01 CA200703]
- Ladies Leukemia League
- American Cancer Society IRG
- Center for Genetic and Genomics
- Center for Inflammation and Cancer
- IRG of UT MD Anderson Cancer Center
- Sister Institution Network Funds of UT MD Anderson Cancer Center
- Tianjin Medical University Cancer Institute and Hospital
- Shanghai Cancer Center
- CPRIT [RP140402, CA100632]
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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy, and T-ALL patients are prone to early disease relapse and suffer from poor outcomes. The PTEN, PI3K/AKT and Notch pathways are frequently altered in T-ALL. PTEN is a tumor suppressor that inactivates the PI3K pathway. We profiled miRNAs in Pten-deficient mouse T-ALL and identified miR-26b as a potentially dysregulated gene. We validated decreased expression levels of miR-26b in mouse and human T-ALL cells. In addition, expression of exogenous miR-26b reduced proliferation and promoted apoptosis of T-ALL cells in vitro, and hindered progression of T-ALL in vivo. Furthermore, miR-26b inhibited the PI3K/AKT pathway by directly targeting PIK3CD, the gene encoding PI3Kd, in human T-ALL cell lines. ShRNA for PIK3CD and CAL-101, a PIK3CD inhibitor, reduced the growth and increased apoptosis of T-ALL cells. Finally, we showed that PTEN induced miR-26b expression by regulating the differential expression of Ikaros isoforms that are transcriptional regulators of miR-26b. These results suggest that miR-26b functions as a tumor suppressor in the development of T-ALL. Further characterization of targets and regulators of miR-26b may be promising for the development of novel therapies.
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