Annals of Clinical & Laboratory Science 35:413-414 (2005)
© 2005 Association of Clinical Scientists
p-p70S6K (Thr 389) Expression in Nodular Sclerosing Hodgkin’s Disease as Evidence for Receptor Tyrosine Kinase Signaling
Robert E. Brown1 and
Nazmi R. Kamal2
1 Division of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania; 2 Princess Iman Research and Laboratory Sciences Center, King Hussein Medical Center, Amman, Jordan
Address correspondence to Robert E. Brown, M.D., Anatomic Pathology, Geisinger Medical Center, 100 North Academy Avenue, Danville, PA 17822-0131, USA; tel 570 214 9781; fax 570 271 6105; e-mail: rebrown{at}geisinger.edu.
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Abstract
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Platelet-derived growth factor receptor-alpha (PDGFR-
) expression in the Hodgkin/Reed-Sternberg cells of nodular sclerosing Hodgkin’s disease has been demonstrated in 2 studies. Additional receptor tyrosine kinases have also now been documented. This communication reports the correlative expression in nodular sclerosing Hodgkin’s disease of activated (phosphorylated) p70S6K, one of the putative downstream effectors common to receptor tyrosine kinase signaling.
Keywords: Hodgkin’s disease, p70S6K, receptor tyrosine kinases
A recent article by Renné et al [1] firmly establishes the expression of PDGFR- in the Hodgkin/Reed-Sternberg (HRS) cells. Moreover, they demonstrated PDGFR- in >90% of their cases of nodular sclerosing Hodgkin’s disease (NSHD). This accords with our previous finding of moderate to strong cytoplasmic expression of PDGFR- antigen in the HRS cells of all 10 cases of NSHD that we studied [2]. Most importantly, Renné et al [1] reported a state of activation for PDGFR- and for 2 other receptor tyrosine kinases (RTK’s), namely TRKA/TRKB, in 43% of cases of NSHD, using antibodies specific to the phosphorylated tyrosine residues on these receptors. Finally, they were able to detect variable expression of other RTK’s in NSHD, including DDR2, EPHB1, and RON [1]. Notably, all 18 of their cases of NSHD expressed at least one RTK; on average, nearly 4 RTK’s per case were expressed [1]. The authors concluded that "tyrosine kinase inhibitors may be potential therapeutic agents for classic HL, especially for NSHL."
Because the serine/threonine kinase p70S6K, when phosphorylated at threonine 389 and translocated to the nucleus, represents a marker of effective RTK downstream signaling through the PI3'-K/Akt/mammalian target of the rapamycin (mTOR) pathway [3–5], we probed for this molecule using an antibody to phosphorylated (p)-p70S6K (Thr 389) [Cell Signaling Technology, Beverly, MA]. Prior IRB approval was obtained for this study.
All 10 of our original cases of NSHD showed moderate to strong chromogenic signal for p-p70S6K (Thr 389) in the nuclei of HRS cells (Fig. 1
). This coincides with the established PDGFR--p70S6K signaling in mesenchymal cells [6] and with the ability of both LY294002, a PI3'-K inhibitor, and rapamycin to reduce the phosphorylation of p70S6K at threonine 389 in Hodgkin KM-H2 cells, as demonstrated by immunocytochemistry and Western blot analysis, respectively [7]. Dutton et al [7], also showed that rapamycin in combination with doxorubicin induced more apoptosis in Hodgkin KM-H2 cells than with doxorubicin alone, leading them to suggest that a combination of rapamycin and chemotherapy should be investigated for the treatment of Hodgkin’s lymphoma.
Although, in principle, we support their suggestion, we are mindful of the work of Zheng et al [8], who documented variable (<10% to >75%) expression of extracellular signal-regulated kinase (ERK) 1/2 phosphorylated at threonine 202, tyrosine 204 in the RS cells of NSHD. Activated ERK 1/2 can contribute to growth promotion by downstream phosphorylation of p-p70S6K and also, independently, through the phosphorylation of nuclear-transcription factors [8,9].
Therefore, we recommend probing NSHD specimens from each patient for the expression of p-p70S6K (Thr 389) and p-ERK 1/2 (Thr 202/Tyr 204). This approach should provide better guidance in designing combinatorial therapies that incorporate small molecule inhibitors of one or both of these downstream signal transduction pathways in conjunction with compatible cytotoxic chemotherapeutic agents.
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Acknowledgements
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The authors thank Glen Kauwell and Laurie Kneller for technical assistance and Sharon Coup for secretarial support.
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