I can see Magneto taking over the school as headmaster trying to repent for the whole Jean Grey fiasco. Storm being co- headmistress. Beast, Iceman, Rogue, Colossus, Kitty, Angel active team members. Wolverine running off again, only to return in the final battle. New mutants could be Emma Frost, Gambit and Sage/Tessa. Throw in Nightcrawler in the final battle too cuz I wanna see the line-up of Storm, Colossus, Kitty, Rogue, Nightcrawler and Wolverine like on the cover of X-Men #210.
The thing I hated most about X3 was Wolverine's obssession with Jean even though she told him that she has Scott in X2. He's over used and should sit out for most of the action in X4. Let Rogue, Angel and Colossus shine.
Villains... Emma Frost, Hellfire Club and Trask/Sentinels.
Of course, also have the cure wear off.
My premise would be the Hellfire Club trying to seize the school for their own purposes, making the X-Men public enemy and therefore having the Sentinels out to hunt them, but the Sentinel programming goes out of control and goes on a mass mutant massacre. Team would be split into two, confronting The Hellfire Club and investigating the Sentinel factory, and reunite in the final battle against the Sentinels on the streets of New York. Kinda lamey, but hey I think it's the best thing I can think of after the crappy events of X3.