Plasma cell tumor induction in mice by pristane is under multigenic control. BALB͞c mice are susceptible to tumor development; whereas DBA͞2 mice are resistant. Restriction fragment length polymorphisms between BALB͞c and DBA͞2 for Cdkn2a(p16) and Cdkn2b(p15), and between BALB͞c and Mus spretus for Cdkn2c(p18 INK4c ) were used to position these loci with respect to the Pctr1 locus. These cyclin-dependent kinase (CDK) inhibitors mapped to a 6 cM interval of chromosome 4 between Ifna and Tal1. C.D2-Chr 4 congenic strains harboring DBA͞2 alleles associated with the Pctr1 locus contained DBA͞2 ''resistant'' alleles of the CDK4͞CDK6 inhibitors p16 and p15. On sequencing p16 and p18 cDNAs, two different allelic variants within ankyrin repeat regions of p16 were found between BALB͞c and DBA͞2 mice. By using an assay involving PCR amplification and restriction enzyme digestion, allelic variants were typed among several inbred strains of mice. One of the variants, G232A, was specific to two inbred strains, BALB͞cAn and ABP͞Le, of mice and occurred in a highly conserved amino acid in both human and rat p16. When tested with wild-type (DBA͞2) p16, both A134C and G232A BALB͞ c-specific variants of p16 were inefficient in their ability to inhibit the activity of cyclin D2͞CDK4 in kinase assays with retinoblastoma protein, suggesting this defective, inherited allele plays an important role in the genetic susceptibility of BALB͞c mice for plasmacytoma induction and that p16 INK4a is a strong candidate for the Pctr1 locus.

The susceptibility of BALB/c mice to pristane-induced plasmacytomas is a complex genetic trait involving multiple loci, while DBA/2 and C57BL/6 strains are genetically resistant to the plasmacytomagenic effects of pristane. In this model system for human B-cell neoplasia, one of the BALB/c susceptibility and modifier loci, Pctr1, was mapped to a 5.7-centimorgan (cM) chromosomal region that included Cdkn2a, which encodes p16INK4a and p19 ARF , and the coding sequences for the BALB/c p16 INK4a and p19 ARF alleles were found to be polymorphic with respect to their resistant Pctr1 counterparts in DBA/2 and C57BL/6 mice (45). In the present study, alleles of Pctr1, Cdkn2a, and D4Mit15 from a resistant strain (BALB/cDAG) carrying DBA/2 chromatin were introgressively backcrossed to the susceptible BALB/c strain. The resultant C.DAG-Pctr1 Cdkn2a D4Mit15 congenic was more resistant to plasmacytomagenesis than BALB/c, thus narrowing Pctr1 to a 1.5-cM interval. Concomitantly, resistant C57BL/6 mice, from which both gene products of the Cdkn2a gene have been eliminated, developed pristane-induced plasma cell tumors over a shorter latency period than the traditionally susceptible BALB/cAn strain. Biological assays of the p16INK4a and p19 ARF alleles from BALB/c and DBA/2 indicated that the BALB/c p16 INK4a allele was less active than its DBA/2 counterpart in inducing growth arrest of mouse plasmacytoma cell lines and preventing ras-induced transformation of NIH 3T3 cells, while the two p19 ARF alleles displayed similar potencies in both assays. We propose that the BALB/c susceptibility/modifier locus, Pctr1, is an "efficiency" allele of the p16 INK4a gene.

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Oral chronic graft-versus-host disease (cGVHD) is a frequent, clinically significant sequela of allogeneic hematopoietic stem cell transplant (HSCT). This study was designed to elucidate relationships among clinical characteristics of oral cGVHD and related oral pain and oral dryness, salivary proinflammatory cytokine IL6 and IL1α concentrations, and health-related quality of life (HRQL). An understanding of the characteristics and correlates of oral cGVHD manifestations and related symptoms such as dryness is fundamental to the development of therapeutic interventions. Methods: Oral cGVHD severity was assessed with the Oral Mucositis Rating Scale (OMRS). Oral pain and perceived oral dryness intensity were self-reported via a visual analogue scale and a numeric rating scale respectively. HRQL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G). Salivary IL1α and IL6 concentrations were measured by enzyme-linked immunosorbent assay (R & D Systems, Minneapolis, MN). Results: All 42 adult subjects (male 59%) had clinician-assessed oral cGVHD by OMRS scale (mean = 18.38 ± 12.99; range = 2 to 46). Oral dryness (43%) (mean = 2.56 ± 3.45; range = 0 to 10) was more prevalent than oral pain (8%) (mean = 0.13 ± 0.47). Salivary IL6 was associated with oral cGVHD severity (r = .49; p < .01), oral ulceration (r = .38; p = .04), and erythema (r = .63; p < .01). FACT-G total, and physical and emotional well-being subscale scores were meaningfully lower than US population normative values. Participants with more severe oral cGVHD manifestations had significantly inferior social/family well-being (r = −.49; p < .01). Oral dryness was associated with higher salivary IL1α (r = .41; p = .04), and controlling for cGVHD severity, with lower health-related quality of life (r = −.41; p = .03). Subjects with moderate to severe oral dryness tended to report the poorest overall HRQL. This study provides preliminary evidence of the relationship between oral dryness and HRQL, the contribution of oral cGVHD to inferior HRQL, and the association between IL6 and oral cGVHD overall severity, ulceration and erythema. The high prevalence of oral dryness and its relationship to HRQL in a sample of patients with oral cGVHD underscores the importance of improving our evaluation and management of this symptom in long-term survivors of allogeneic HSCT. The positive association seen between IL6 and oral sGVHD overall severity, and erythema, as well as the positive trend seen with oral ulceration, warrant further exploration of this cytokine as a potential biomarker of active oral cGVHD.