The three latter letters are usually meaningful, but only barely. For example, there’s WGBH, a Boston public broadcasting station that stands for Great Blue Hills, which are the hills that the broadcasting antenna is located on.

You can request a call sign along with getting your license from the FCC. The process has changed over time, but many (most?) call signs have some sort of historical connection to something: e.g. KRON was broadcast from the SF Chronicle newspaper building, WRCT is Carnegie Mellon's University's station (originally Radio Carnegie Tech, from before it was CMU). https://en.wikipedia.org/wiki/Call_signs_in_the_United_State...

It seems to go in both directions: you can ask for one that has some meaning to you (which you can then potentially get if no one is using it), or you can try to make up a backronym. I don't remember good backronym examples but I know they exist. The stations will also vary in whether they prefer for people to pronounce the whole callsign, or just part of it, or spell it out. (Technically I think the callsign is always spelled out when used as a callsign, but not necessarily when used as a brand.)