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Acute lymphoblastic leukemia

Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD

Leukemia volume 31, pages 2355–2364 (2017)Cite this article

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Abstract

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 PI3Kδ, 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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Acknowledgements

This work was partially supported by NIH/NCI R01 CA164346, R01 CA200703, CPRIT RP140402 Developmental Research Awards in Leukemia SPORE CA100632, Ladies Leukemia League, and American Cancer Society IRG, Center for Genetic and Genomics, Center for Inflammation and Cancer, Physician Scientist Award and IRG of UT MD Anderson Cancer Center to MJY. This work was also supported by the Sister Institution Network Funds of UT MD Anderson Cancer Center to MJY, and matching fund from Tianjin Medical University Cancer Institute and Hospital to YZ and matching fund from Shanghai Cancer Center to XYZ. The postnatal normal thymocytes were generously provided by Dr Andrew P Weng at Terry Fox Laboratory. The CCRF-CEM-FFluc cell line was kindly provided by Dr Malcolm K Brenner at Texas Children’s Hospital and Houston Methodist Hospital, Houston, TX, USA. miRNA expression profiling was performed at the core for Sequencing and ncRNA Program at the University of Texas MD Anderson Cancer Center. RNAseq was performed at the Sequencing and Microarray Facility at the University of Texas MD Anderson Cancer Center.

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  1. P A Zweidler-McKay

    Present address: 16Current address: ImmunoGen Inc., Waltham, MA, USA.,

Authors and Affiliations

  1. Department of Hematopathology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    T Yuan, Y Yang, J Chen, W Li, W Li, R S Goswami, D Lin, S Calin, Y Liang, R N Miranda, L J Medeiros & M J You

  2. Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    T Yuan & Y Zhang

  3. Shaoxing University Medical School, , Shaoxing City, Zhejiang Province, China

    J Chen & Y Liang

  4. Department of Laboratory Medicine, Harbin Medical University Tumor Hospital, Harbin, Heilongjiang Province, China

    W Li

  5. Department of Leukemia, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Q Zhang & Y Mi

  6. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    R S Goswami

  7. Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J Q You

  8. Department of Immunology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    D Lin

  9. Department of Experimental Therapeutics and Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M D Qian & G A Calin

  10. Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China

    X Zhou

  11. Department of Experimental Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    L Ma

  12. Division of Pediatric, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P A Zweidler-McKay

  13. Department of Genetics, the University of Texas MD Anderson Cancer Center, Houston, TX, USA

    B Liu

  14. Department of Pathology and Laboratory Medicine, the University of British Columbia, Vancouver, BC, Canada

    A P Weng

  15. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA

    M J You

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Correspondence to Y Zhang or M J You.

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Yuan, T., Yang, Y., Chen, J. et al. Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia 31, 2355–2364 (2017). https://doi.org/10.1038/leu.2017.80

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