This is the perfect location for five reasons
1. Untouched by previous FO games. You can still have BoS and Enclave, but no NCR or Followers or whatever, but you can have new and interesting factions. This means we can avoid the semi-domesticated feeling that the NCR gives.
2. Easily expandable (great lakes (canol), gulf region, ohio river, etc) The missouri river actually takes you all the way to Montana. The arkansas river begins in Colorado. This starting location allows you to explore really all the US east of the Rockies.
3. Plausible fast travel. If the game was based in Seattle and I wanted to go to Colorado (expansion maybe) then its just like...did I take a Vertibird?...did the 4000 other players who did the same thing also take a Vertibird? With the Miss you just took a steam boat, a raft, a sail boat, a slave or brahmin powered boat, or an Enclave Destroyer .
4. Varied terrains. You can have expansive forests, subtropical swamps, deserts (new since the war), snow, If you go over to Colorado and Montana you can even have mountains.
5. You have four major cities; Minneapolis, Memphis, St. Louis, and New Orleans. This gives you a lot of variety of places to explore. On the sad side no easy puns like The Pitt
Well what do you think? All I want for Christmas is APA and a gauss rifle.