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Kapoor I, Bodo J, Hill BT, et al. Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies. Cell Death Dis. 2021;12(11):1061doi: 10.1038/s41419-021-04353-9.
Kapoor, I., Bodo, J., Hill, B. T., & Almasan, A. (2021). Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies. Cell death & disease, 12(11), 1061. https://doi.org/10.1038/s41419-021-04353-9
Kapoor, Isha, et al. "Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies." Cell death & disease vol. 12,11 (2021): 1061. doi: https://doi.org/10.1038/s41419-021-04353-9
Kapoor I, Bodo J, Hill BT, Almasan A. Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies. Cell Death Dis. 2021 Nov 08;12(11):1061. doi: 10.1038/s41419-021-04353-9. PMID: 34750354; PMCID: PMC8575967.
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Cell Death Dis. 2021 Nov 08;12(11):1061. doi: 10.1038/s41419-021-04353-9.

Cooperative miRNA-dependent PTEN regulation drives resistance to BTK inhibition in B-cell lymphoid malignancies.

Cell death & disease

Isha Kapoor, Juraj Bodo, Brian T Hill, Alexandru Almasan

Affiliations

  1. Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA.
  2. Department of Laboratory Medicine, Institute of Pathology and Laboratory Medicine, Cleveland, OH, USA.
  3. Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland, OH, USA.
  4. Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, USA. [email protected].
  5. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. [email protected].

PMID: 34750354 PMCID: PMC8575967 DOI: 10.1038/s41419-021-04353-9

Abstract

Aberrant microRNA (miR) expression plays an important role in pathogenesis of different types of cancers, including B-cell lymphoid malignancies and in the development of chemo-sensitivity or -resistance in chronic lymphocytic leukemia (CLL) as well as diffuse large B-cell lymphoma (DLBCL). Ibrutinib is a first-in class, oral, covalent Bruton's tyrosine kinase (BTK) inhibitor (BTKi) that has shown impressive clinical activity, yet many ibrutinib-treated patients relapse or develop resistance over time. We have reported that acquired resistance to ibrutinib is associated with downregulation of tumor suppressor protein PTEN and activation of the PI3K/AKT pathway. Yet how PTEN mediates chemoresistance in B-cell malignancies is not clear. We now show that the BTKi ibrutinib and a second-generation compound, acalabrutinib downregulate miRNAs located in the 14q32 miRNA cluster region, including miR-494, miR-495, and miR-543. BTKi-resistant CLL and DLBCL cells had striking overexpression of miR-494, miR-495, miR-543, and reduced PTEN expression, indicating further regulation of the PI3K/AKT/mTOR pathway in acquired BTKi resistance. Additionally, unlike ibrutinib-sensitive CLL patient samples, those with resistance to ibrutinib treatment, demonstrated upregulation of 14q32 cluster miRNAs, including miR-494, miR-495, and miR-543 and decreased pten mRNA expression. Luciferase reporter gene assay showed that miR-494 directly targeted and suppressed PTEN expression by recognizing two conserved binding sites in the PTEN 3'-UTR, and subsequently activated AKT

© 2021. The Author(s).

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