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The Role of the PI3K Pathway in Anti-IgM (Anti-µ) -Sensitive and -Resistant B-cell Lymphomas

Failure to Disengage PI3K Pathway Signaling Confers Anti-µ Resistance on the CH12 B Cell Lymphoma

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Molecular Mechanisms of Programmed Cell Death

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Abstract

We and others have firmly established that surface IgM receptor (sIgM-R) crosslinking leads to growth arrest and apoptosis in a series of well characterized B lymphomas. This requires ablation of c-Myc protein expression and the concomitant induction of the CKI, p27Kip1. The signaling mechanisms regulating c-Myc and p27Kip1 protein expression are poorly understood. However, we recently established that sIgM-R mediated down-modulation of the PI3K pathway directly affected c-Myc and p27Kip1 expression and accurately predicted growth arrest or apoptosis in the ECH408 B lymphoma line. Moreover, p27-TAT fusion protein (which is rapidly taken up by these lymphoma lines) disappeared rapidly in growing B-lymphoma lines, but it persisted in the presence of anti-m. We have now extended these studies to the well-characterized CH12 B-lymphoma cell line, which is resistant to anti-m induced growth arrest and apoptosis, despite its sIgM-Rhigh phenotype. The results show that failure to inactivate p70S6K and to activate GSK3-b, results in anti-m resistance. Blockade of PI3K, or an upstream regulator of p70S6K, mTOR, reconstitutes or mimics all negative sIgM receptor signaling in these cells. Finally, anti-m or PI3K blockade induces PTEN protein expression especially in the WEHI-231 B-cell line. Together, these results reveal apparently fundamental mechanisms for inducing immune tolerance (PI3K suppression leading to anergy or deletion), or activation (stimulation of or maintenance of PI3K activity), or lymphomagenesis (failure to disengage PI3K signaling).

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Abbreviations

Anti-m:

anti-mu (IgM) heavy chain

-m:

anti-delta (IgD) heavy chain

BCR:

B-cell antigen receptor

CKI:

cyclin dependent kinase inhibitor

p27Kip1 :

27kDa cyclindependent kinase inhibitor

p70S6K :

70kD isoform of ribosomal protein S6, kinase

MIgM, MIgD:

membrane

IgM:

membrane

PI3K:

Phosphatidylinositol 3 kinase

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Authors and Affiliations

  1. Department of Immunology, Holland Laboratory of the American Red Cross, Rockville, MD, 20855, USA

    Gregory B. Carey, Laura Tonnetti & Dr. David W. Scott

  2. Department of Immunology, George Washington University School of Medicine, Washington, DC, 20037, USA

    Dr. David W. Scott

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  1. Gregory B. Carey
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  2. Laura Tonnetti
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  3. Dr. David W. Scott
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Correspondence to David W. Scott .

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Editors and Affiliations

  1. Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA

    Yufang Shi

  2. National Institutes of Health, Research Triangle Park, North Carolina, USA

    John A. Cidlowski

  3. American Red Cross, Rockville, Maryland, USA

    David Scott

  4. Chinese Academy of Sciences, Shanghai, China

    Jia-Rui Wu

  5. National Institutes of Health, Bethesda, Maryland, USA

    Yun-Bo Shi

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Carey, G.B., Tonnetti, L., Scott, D.W. (2003). The Role of the PI3K Pathway in Anti-IgM (Anti-µ) -Sensitive and -Resistant B-cell Lymphomas. In: Shi, Y., Cidlowski, J.A., Scott, D., Wu, JR., Shi, YB. (eds) Molecular Mechanisms of Programmed Cell Death. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-5890-0_4

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