Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia

Abstract

Gain-of-function mutations in NOTCH1 are common in T-cell lymphoblastic leukemias and lymphomas (T-ALL), making this receptor a promising target for drugs such as γ-secretase inhibitors, which block a proteolytic cleavage required for NOTCH1 activation. However, the enthusiasm for these therapies has been tempered by tumor resistance and the paucity of information on the oncogenic programs regulated by oncogenic NOTCH1. Here we show that NOTCH1 regulates the expression of PTEN (encoding phosphatase and tensin homolog) and the activity of the phosphoinositol-3 kinase (PI3K)-AKT signaling pathway in normal and leukemic T cells. Notch signaling and the PI3K-AKT pathway synergize in vivo in a Drosophila melanogaster model of Notch-induced tumorigenesis, and mutational loss of PTEN is associated with human T-ALL resistance to pharmacological inhibition of NOTCH1. Overall, these findings identify transcriptional control of PTEN and regulation of the PI3K-AKT pathway as key elements of the leukemogenic program activated by NOTCH1 and provide the basis for the design of new therapeutic strategies for T-ALL.

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Figure 1: PTEN loss and AKT activation in GSI-resistant T-ALLs.
Figure 2: PTEN loss and AKT activation induce GSI resistance in T-ALL.
Figure 3: NOTCH1 regulates PTEN expression, AKT signaling and glucose metabolism.
Figure 4: HES1 and MYC regulate PTEN expression downstream of NOTCH1.
Figure 5: Interaction of Notch and Pten-PI3K-Akt signaling in growth control and tumorigenesis in Drosophila.
Figure 6: Transcriptional networks downstream of NOTCH1 in T-ALL and effects of pharmacologic inhibition of AKT in T-ALL cells.

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Acknowledgements

We thank A.T. Look (Dana-Farber Cancer Institute) and M. Minden (Ontario Cancer Institute) for valuable clinical samples; D. Ferres-Marco (Instituto de Neurociencias de Alicante) for the GS1D233C line; E. Ballesta (Instituto de Neurociencias de Alicante) for histological sections of dDp110; T. Yoshimori (Kansai Medical University), R. Dalla Favera, W. Ai and D. Accili (Columbia University) and W. Hahn (Dana-Farber Cancer Institute) for reagents; V. Miljkovic for assistance with DNA sequencing and microarray hybridization; and B. Weinstein, R. Baer, T. Diaccovo and C. Lopez-Otin for critical review of the manuscript. This work was supported by the Fondazione Città Della Speranza (G. Basso), the Spanish Ministerio de Educacion y Ciencia and Asociación Española Contra el Cancer (M.D.), NIH grant CA120196, the WOLF Foundation, the Charlotte Geyer Foundation, the Golfers Against Cancer Foundation and the Leukemia and Lymphoma Society (grant 1287-08) (A.A.F.). Adolfo Ferrando is a Leukemia & Lymphoma Society Scholar.

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Correspondence to Maria Dominguez or Adolfo A Ferrando.

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Supplementary Results, Supplementary Discussion, Supplementary Methods, Supplementary Figs. 1–10, Supplementary Tables 1–5, Supplementary Methods (PDF 2893 kb)

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Palomero, T., Sulis, M., Cortina, M. et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13, 1203–1210 (2007). https://doi.org/10.1038/nm1636

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