Oncogenic network of NKX2-1.

<p>The figure summarizes the regulations of the genes described in this study, highlighting a central position of NKX2-1. Chromosomal aberrations activate expression of MLL (11q23) and histones including H2B (6p22). MLL together with H2Bub1 generate an activatory chromatin structure at NKX2-1. This structure is reinforced by reduced expression of USP46 and E2F6 and elevated expression of RNF20/40, JMJD3 and HOPX, and mediates activation of NKX2-1. NKX2-1 in turn activates directly expression of HEY1 which performs inhibition of B-cell differentiation. Both, NKX2-1 and HEY1 contribute to the activatory chromatin structure by regulating RNF40 and E2F6, respectively. IL4/STAT3-signaling enhances expression of NKX2-1. TNFa, cGMP, cAMP and PRKCE support NFkB which activates both NKX2-1 and HEY1. Reduced expression of PDE6D and enhanced expression of NOS1 contribute to elevated cGMP. NOS1 and PRKCE are activated by NKX2-1. HEY1 mediates reduced expression of PDE4A resulting in elevated cAMP levels. Finally, NOTCH-signaling and TGFb-signaling (via SMAD) activate HEY1 expression. SMAD and NKX2-1 interact and coactivate HEY1 transcription.