You'd focus it on maybe 25 cities (more if profitable, later), for sure, but you'd need at least one transnational route for it to be profitable, becuse thats where it would make the difference.
Basically, you'd have three districts.
West
Seattle-Portland-Sacramento-San Francisco-Los Angeles-San Diego-Pheonix
Central
Los Angeles-Denver-St. Louis-Chicago-Cleveland-Philadelphia
East
Boston-NYC-Philadelphia-Baltimore
With possible extensions/more stations:
West
Vancouver-Seattle-Portland-Sacramento-San Francisco-Los Angeles
-San Diego-Pheonix-Albuquerque-Denver
Central
Los Angeles-Las Vegas-Salt Lake City-Denver-Topeka-St. Louis-Chicago-Cleveland-Pittsburgh-Philadelphia
offshoot: Topeka-Oklahoma City-Dallas-Houston
offshoot: Dallas-New Orleans-Mobile-Orlando
offshoot: St. Louis-Memphis-Atlanta-Orlando-Tampa-Miami
offshoot: Chicago-Milwaukee-Minneapolis
offshoot: St. Louis-Indianapolis-Detroit
offshoot: Indianapolis-Pittsburgh
East
Boston-Hartford-NYC-Philadelphia-Batimore-Richmond-Raleigh-Atlanta
offshoot: NYC-Buffalo-Toronto-Montreal
So, Basically, start with Seattle-Portland-Sacramento-San-Francisco-Los Angeles, Los-Angeles-Denver-St. Louis-Chicago-Philadelphia, Boston-NYC-Philadelphia-Baltimore, and then as demand neccessitates, add the offshoots. The main hubs would be Los Angeles, Denver, St. Louis, Chicago, and Philadelphia, with second-stage and secondary hubs in NYC, Atlanta, Dallas, and Topeka; with other hubs created if/when necessary.
That make sense to everyone out there?