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
  • Gregory B. Carey
  • Laura Tonnetti
  • David W. Scott


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).


Growth Arrest PI3K Pathway PI3K Signaling sIgM Receptor Induce Growth Arrest 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



anti-mu (IgM) heavy chain


anti-delta (IgD) heavy chain


B-cell antigen receptor


cyclin dependent kinase inhibitor


27kDa cyclindependent kinase inhibitor


70kD isoform of ribosomal protein S6, kinase






Phosphatidylinositol 3 kinase


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Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Gregory B. Carey
    • 1
  • Laura Tonnetti
    • 1
  • David W. Scott
    • 1
    • 2
  1. 1.Department of ImmunologyHolland Laboratory of the American Red CrossRockvilleUSA
  2. 2.Department of ImmunologyGeorge Washington University School of MedicineUSA

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