The Route 1333 bus was heading through New Mexico and Arizona, with final scheduled stops in San Bernardino and downtown Los Angeles. There were 49 passengers on board, according to Greyhound.
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The bus had left St. Louis Wednesday morning, according to its route schedule. It was on the way to Phoenix when the crash occurred.
Preliminary information indicated the semi was headed east when it blew a tire, sending the rig across the median and into oncoming traffic where it smashed into the bus, New Mexico State Police said.
Earlier on, the police said there were four casualties, but the number increased to seven by Thursday night.
There were 42 people transported to local hospitals and six treated for minor injuries at the scene.
The wreckage included a Greyhound bus with front-end damage and a semi-truck that was on its side and with its cargo strewn across the highway and the median.
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Greyhound spokeswoman Crystal Booker says it's unclear what caused the crash.
"We are fully cooperating with local authorities and will also complete an investigation of our own," Booker said in a statement.
The crash forced the closure of the westbound lanes of the interstate and traffic was backing up as travelers were being diverted.
Chris Jones was headed west on Interstate 40 when he caught his first glimpse of the semi turned over. He saw the rest of the wreckage and stopped to help before coming across the driver of the semi sitting on the shoulder of the highway.
"It was intense," Jones said.
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He said the driver told him that one of his front tires had popped, forcing the truck to veer into oncoming traffic, where it struck the bus.
The crash occurred near the town of Thoreau. It forced the closure of the westbound lanes of the interstate and traffic was backing up as travelers were diverted.
UPDATE: Greyhound initially said there were 47 passengers on board. This story has been updated to reflect the company now says there were 49.
The Associated Press contributed to this report.