In an article published by Dr. Pittaluga in our group, highlighted on the cover of Modern Pathology, Quantum dots were utilized as a useful alternative method to traditional organic fluorophores. Dr. Pittaluga found that multispectral staining showed high specificity, low background and high emission intensity. Moreover, the relatively narrow emission peaks of Streptavidin labeled Quantum dots (Q dots) allowed the use of multiple (3 to 5) antibodies on a single tissue section. This technique was applied in routinely processed paraffin-embedded sections, and examined by confocal microscopy. The ability to image multiple antigens simultaneously is likely to prove to be a powerful new tool for research and diagnosis. This study was highly praised by the reviewers for its innovations and potential for research applications. To determine whether the PI3-kinaase (PI3K)/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), Dr. Raffeld investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12/12 aggressive blastoid MCL variants and in 4/4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5/16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27(kip1), FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27(kip1), FRKHL-1, MDM2, Bad, mTOR, GSK-3beta, IkappaB, and led to cell cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and one with inactive Akt), and 3/4 cell lines showed loss of PTEN expression. PI3KCA mutations were not detected. These data suggest that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL, and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL, and identify potential new molecular targets for therapy. Dr. Raffeld also explored signaling pathways in anaplastic large cell lymphoma (ALCL), the most common type of peripheral T-cell lymphoma. C/EBPbeta is one of a six-member family of CCAAT/enhancer binding proteins (C/EBP). These transcription factors are involved in the regulation of various aspects of cellular growth and differentiation. Although C/EBPbeta has important functions in both B and T-cell differentiation, its expression has not been well studied in lymphoid tissues. We, therefore, analyzed its expression by immunohistochemistry and/or Western blot in normal lymphoid tissues and in 248 well characterized lymphomas and lymphoma cell lines. Non- neoplastic lymphoid tissues and the vast majority of B- cell, T-cell, and Hodgkin lymphomas lacked detectable C/EBPbeta. In contrast, most cases of ALK-positive ALCL (40/45; 88%) strongly expressed C/EBPbeta. These data suggest that C/EBPbeta is likely to play an important role in the pathogenesis and unique phenotype of this lymphoma.
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