It says something that I'm so out of touch with my comics habit that this thread is how I found out about it.
They have to handle this with care. Fold up the old world with dignity and... I hate to say it... let some of their most beloved themes rest in peace. If they're going to run this risk they can't go halfway on it: "We're starting over... but keeping everything exactly the same!" won't comfort old fans and won't interest new ones. "We're changing everything just to make people realize how extreme our reboot is!" is something DC already tried a couple times...
The X-Men being "a family united by adversity" is a theme that's too central to eliminate, but the 'constant irrational racism' theme that never lets them get any credit could stand a rest for a few decades. Spider-Man being a self-critical underdog? That has to stay - it's central - but his personal life being in a constant state of crisis could be given a rest. The Fantastic Four being explorers, problem-solvers and inseparable companions is fundamental: having superpowers, odd as it sounds, isn't really essential.
And above all, no messing with Doom. As he'd be the first to tell you, he's perfect as he is.
I think this is going to come down to bringing in popular parts of the Ultimates and various non Universe 616 elements (Spider-Gwen) into a new shared Marvel Universe, as well as retconning some of the less popular elements. Also probably setting up MCU friendly storylines and characters.