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Referee Comments: Referee 3 (Atan Gross)

Posted by PLOS_ONE_Group on 08 Apr 2008 at 22:05 GMT

Referee 3's Review (Atan Gross):

The authors of this manuscript show a striking phenotype: Bcl-2 synergistically cooperates with p27 deficiency to increase spontaneous T cell lymphoma. Unfortunately, the authors could not find a mechanistic explanation for this phenotype. Most of their studies to reveal an explanation were performed in-vitro using purified T cells activated with anti-CD3. I suggest that the authors also examine whole tissue sections taken from the different mice for proliferation (BrdU, Ki67, and phospho-histone H3 staning), apoptosis (TUNEL and anti-cleaved caspase-3 staining), and expression levels of cell cycle regulators. Such an analysis of tissue sections might reveal differences between the p27+/-Lck-Bcl-2 and p27-/-Lck-Bcl-2 mice.

N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.

RE: Referee Comments: Referee 3 (Atan Gross)

knudsonm replied to PLOS_ONE_Group on 14 Apr 2008 at 13:23 GMT

Dr Gross is pointing out the fact that we do not see an effect of p27 deficiency on proliferation of T cells in the adult Bcl-2 transgenic mice. Yet we do see a dramatic increase in tumors in these same mice. In response we have analyzed the cell cycle data by age and show that in younger mice we do find an increase in the percentage of proliferating cells in p27 deficient mice. This ties in nicely with our data showing an increase in T cell hyperplasia in the p27 deficient Lck-Bcl-2 transgenic mice. Based on this, we propose that p27 deficiency results in increased T cell proliferation during development and that leads to T cell hyperplasia. We propose that the increase in T cell numbers at least in part explains the increase in lymphoma development.