Susceptibility/resistance to plasmacytomagenesis is a complex genetic trait. In earlier linkage studies, Pctm, a modifier of plasmacytoma susceptibility, was associated with heterozygosity of Chr 1 genes. In the current study, we identified genes on Chr 1 that were differentially expressed in the oil granulomatous tissues where the tumors arise, between resistant and susceptible strains of mice in response to the tumor inducer, pristane. Two of the most differentially expressed genes between the strains were a novel murine hematopoietic interferon inducible protein sharing homology with human MNDA, we designated Mndal for MNDA-like (myeloid nuclear differentiation antigen like) and the interferon inducible gene, Ifi203. Mndal and Ifi203 are both located in the IFI/HIN-200 cluster on mouse Chr 1 (band H3). Mndal's expression was >1000-fold higher in BALB than in DBA inflammatory tissues;Ifi203 was also differentially expressed but to a lesser degree. Genomic sequence analysis revealed that Mndal was absent from the DBA genome, and so were the 5 regions of Ifi203. Ectopic expression of the BALB Mndal gene in murine cells suppressed growth, pristane induced higher levels of Mndal in vivo, and interferon induced a higher level of expression in BALB3T3 cells. These activities, together with the disease susceptibility of heterozygotes at the Pctm locus, suggest that Mndal or a combination of Mndal and Ifi203 act as a tumor suppressor(s) and display(s) haplo-insufficiency. The absence of Mndal or the combination of Mndal/Ifi203 should also be examined as a potential cause for other disease phenotypes, such as modifiers of autoimmunity as well as, lung, colon and skin cancer risk, which also map within the same interval on mouse Chr 1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011064-06
Application #
8763331
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$196,500
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
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State
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