Figure 7.

Nkx2-1 (NK2 homeobox 1) is essential for development of small-cell lung cancer (SCLC) subtype SCLC-Aα tumors in an autochthonous mouse model. (A) Genetically engineered mouse models of SCLCs. Rb1^flox/flox; Trp53^flox/flox (RP) mice or Rb1^flox/flox; Trp53^flox/flox, Nkx2-1^flox/flox (RPN) mice were transduced with Adeno-CMV-Cre to initiate SCLC. (B) Genome view tracks at the Nkx2-1, Sox1 (SRY-box transcription factor 1), and Ascl1 (achaete-scute homolog 1) loci for H3K27ac chromatin immunoprecipitation followed by sequencing signals in 10 SCLC tumors from RP mice and 10 SCLC tumors from RPN mice. Asterisk indicates three tumors that have high signal at both Nkx2-1 and Sox1 loci. The arrowheads on Nkx2-1 locus indicate the loxP sites in RPN mice. (C) Representative immune-staining images for Nkx2-1, Sox1, and Ascl1 on SCLC tumors from RP and RPN mice. Scale bars, 25 μm. (D) Representative H&E images of SCLC tumors from RP and RPN mice. Scale bars, 50 μm. (E) Enriched gene ontologies (Molecular Signatures Database biological process) for the differentially downregulated genes in RPN tumors compared with RP tumors. (F) Average copy number profiles in RP and RPN models. Arrows indicate the Nfib (nuclear factor I B) and Mycl (Mycl proto-oncogene, BHLH transcription factor) loci that are specifically amplified in RP tumors (individual copy number profiles at those loci are available in Figure E8D). chr = chromosome; CMV = cytomegalovirus; H&E = hematoxylin and eosin.