Abstract Our laboratory recently showed that elevated TS plays a direct causal role in tumorigenesis of NIH3T3 cells in vitro and in the development of endocrine pancreatic mouse tumors in vivo. This observation changed the paradigm of TS as a passive biomarker and has significance for cancer treatment as it refocuses attention on the importance of TS as a tumor-promoting signal. To address whether TS plays an early role in tumorigenesis that is restricted to specific tumor types or if TS plays a late role associated with enhanced progression of established tumors of diverse histologic origin, we have now cross-bred human TS (hTS) transgenic mice with Ink4a/Arf null mice, a common somatic mutation frequently found in adult human cancers. Median survival of hTS/Ink4a/Arf+/- (n=15) mice was reduced 24% (313 vs. 411 days, p <0.05). Both hTS/Ink4a/Arf+/- and hTS/Ink4a/Arf-/- mice (n=16) showed an increase in lymphoma, histiocytic sarcoma (HS) and soft tissue sarcoma (SS). For example, the incidence of HS in hTS/Ink4a/Arf-/- male mice was 31% versus 12% in Ink4a/Arf-/- minus (p<0.01), and tumor cells had spread to multiple tissues (as many as 9 different organs) as compared to hTS minus mice where tumors were localized in lymph nodes and spleen. Strikingly, the tumor burden was markedly increased in hTS/Ink4a/Arf-/- mice: average spleen weight 1.11 vs. 0.49 g, p<0.001, lymph nodes, 1.06 g vs. 0.42 g, p<0.001. We also detected an increase in size and extent of tumor mass of SS (average weight 5.8 g). We detected increased aneuploidy in hTS/Ink4a/Arf-/- HS cell lines as compared to Ink4a/Arf-/- HS cell lines: chromosomal loss 32.1% vs. 16.7%, p<0.05, gain 24.5% vs. 0%, p<0.001 and translocations 9.4% vs. 0%, p<0.05 by spectral karyotyping analysis. Treatment of TS positive HS tumor cells with lenti-TS shRNAs downregulated TS expression and resulted in tumor growth inhibition in vitro as well as in mouse orthotopically transplanted xenograft. In addition, combined TS shRNAs with gemcitabine or pemetrexed treatment showed synergistic inhibition of HS tumor cell growth. These data demonstrate that deregulated TS enhanced genome instability and promote tumor progression in diverse hematopoietic and mesenchymal tumor cells. Citation Format: Min Chen, Akbar Nawab, Frederic J. Kaye, Maria Zajac-Kaye. Deregulated TS promotes tumor progression in diverse hematopoietic and mesenchymal cell lineages. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2014-2042