The Ink4a͞Arf locus encodes p16 Ink4a and p19 Arf and is among the most frequently mutated tumor suppressor loci in human cancer. In mice, many of these effects appear to be mediated by interactions between p19 Arf and p53, Ink4a͞Arf expression correlates with or precedes the emergence of cells expressing mutant p53. These data demonstrate that p19 Arf is an important part of the cellular defense mounted against transforming signals from the Abl oncoprotein and provide direct evidence that the p19 Arf -p53 regulatory loop plays an important role in lymphoma induction.

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Transformation of pre-B cells by Abelson murine leukemia virus (Ab-MLV) involves a balance between positive, growth-stimulatory signals from the v-Abl oncoprotein and negative regulatory cues from cellular genes. This phenomenon is reflected by the clonal selection that occurs during Ab-MLV-mediated transformation in vivo and in vitro. About 50% of all Ab-MLV-transformed pre-B cells express mutant forms of p53 as they emerge from this process, suggesting that this protein may play an important role in the transformation process. Consistent with this idea, expression of p19(Arf), a protein whose function depends on the presence of a functional p53, is required for the apoptotic crisis that characterizes primary Ab-MLV transformants. To test the role of p53 in pre-B-cell transformation directly, we examined the response of Trp53(-/-) mice to Ab-MLV. The absence of p53 shortens the latency of Abelson disease induction but does not affect the frequency of cells susceptible to Ab-MLV-induced transformation. However, primary transformants derived from the null animals bypass the apoptotic crisis that characterizes the transition from primary transformant to fully malignant cell line. These effects do not require p21(Cip-1), a major downstream target of p53; however, consistent with a role of p19(Arf), transformants expressing mutant p53 and abundant p19 retain wild-type p19 sequences.

Purpose: Signal transducer and activator of transcription 5 (STAT5) and STAT3 oppose one another in regulation of the reciprocal development of CD4 + CD25 + FOXP3 + regulatory T cells (Treg) and T helper 17 (Th17). A reduction in STAT3 is associated with up-regulation of Treg, and STAT5 activation promotes T reg differentiation or function while constraining Th17 generation. The effects of IFNa on STAT signaling in relation to tumor tissue T reg and Th17 have not been documented in humans beyond the observations that IFNa2b down-regulates STAT3. Experimental Design: Following diagnostic biopsy and before definitive surgery, 20 doses of high-dose IFNa2b (HDI) were administered to patients with stage IIIB melanoma who gave written informed consent. Lymph node biopsies, in which both total STAT3 and phosphorylated STAT3 were down-regulated by HDI, were probed with STAT5, FOXP3, CD4, and interleukin 17 (IL-17) with immunohistochemistry and/or immunofluorescence techniques. Results: The percentage of FOXP3+ lymphocytes determined by immunohistochemistry was up-regulated from 3.06 F 0.65% to 9.86 F 1.27% (n = 13, P = 0.0002), and this observation was confirmed by immunofluorescence evaluation of CD4 + FOXP3+ Tregs. HDI induced STAT5 up-regulation (five cases observed) in melanoma cells and lymphocytes but did not induce the generation of IL-17^expressing lymphocytes. Increased STAT5 expression was associated with increased FOXP3 expression among lymphocytes, and STAT5 was constitutively activated among both melanoma cells and lymphocytes. Conclusion: IFNa2b up-regulates STAT5 and down-regulates STAT3, in conjunction with up-regulation of T reg and inhibition of IL-17^expressing lymphocytes in melanoma tissues. These findings suggest that the effects of IFNa may be potentiated through interference with the response of Tregs and/or STAT5.

The oncocyte is a cell characterized by capacious, eosinophilic, finely granular cytoplasm, and lesions composed primarily of oncocytes are termed oncocytomas. Whereas oncocytic metaplasia has been reported in various cutaneous neoplasms, oncocytomas typically occur in the kidneys, thyroid and salivary glands and are uncommon in the dermatopathology literature. We present three cases of cutaneous oncocytoma so that dermatopathologists are cognizant of this uncommon entity. Although some believe that oncocytomas are locally aggressive lesions, our cases indicate that their clinical course is perhaps as banal as their histology.