DDNews Cancer Research Exclusive: From bad to good

A team of researchers has discovered a way to turn leukemia cells into standard immune cells known as macrophages, a type of white blood cell. The type of cancer featured in this paper—specifically, B-cell acute lymphoblastic leukemia with the Philadelphia chromosome mutation—is a particularly aggressive cancer of the white blood cells. What makes this new approach possible is that it is also, in a way, a very immature cancer on a cellular level.

“B-cell leukemia cells are, in many ways, progenitor cells that are forced to stay in an immature state,” said Dr. Ravi Majeti, an assistant professor of medicine at Stanford and senior author of the recent paper. Majeti is also a member of the Stanford Cancer Institute and the Stanford Institute for Stem Cell Biology and Regenerative Medicine.

This discovery came about when Majeti's team was studying leukemia cells in dishes. Postdoctoral scholar Dr. Scott McClellan, one of the paper's lead authors, noticed that some of the cells were changing in size and shape into what appeared to be macrophages. Recalling a previous paper that demonstrated that early B-cell mouse progenitor cells could be transformed into macrophages in the presence of certain transcription factors, Majeti, along with McClellan and Christopher Dove, an M.D./Ph.D. student and another lead author for the paper, conducted experiments that confirmed those methods could be used to transform human cancer cells into macrophages.

“They do it by binding to, presumably, the extracellular cytokine receptors, which are able to trigger some sort of transcriptional change within the cells,” explains Dove. “Ordinarily you wouldn't think of B-cell blasts having some of these cytokine receptors, but ostensibly they do in high enough concentrations to induce this change. The mechanism by which that's happening we speculate to be mediated through a myeloid transcription factor, probably C/EBPα, but that's something we haven't validated yet.”

The transcription factors involved in this process, according to Dove, play roles in the growth and development of myeloid cells, including “standard monocyte macrophage development.”

And while the ability to turn cancerous cells into healthy immune cells is promising enough on its own, there's also some potential that these erstwhile cancer cells, in their new macrophage state, could be particularly well suited for fighting cancer.

“Because the macrophage cells came from the cancer cells, they will already carry with them the chemical signals that will identify the cancer cells, making an immune attack against the cancer more likely,” Majeti said.

“It's something we're starting to look into already,” Dove adds. “These cells, in addition to myeloid surface markers like CD14, which is a common co-receptor for bacterial antigens, they will also express co-receptors for the stimulation of other immune cells—for example, is CD86 and CD40, which are co-stimulatory molecules that interface with T cells. So we haven't looked into whether or not these macrophage-like cells have any direct effect on T cells, but the machinery is at least there.”

Moving forward, the team will investigate whether they can identify a drug that can elicit the same reaction and possibly provide a new leukemia therapy. While Dove says there aren't any drugs on the market currently that can elicit the reaction they're hoping for, he notes that “there are hints about small molecules that would be able to increase and stabilize a myeloid phenotype.”

“I'm of the opinion that these cells, because they are fairly undifferentiated, just need a degree of perturbation before adopting a myeloid phenotype, and it doesn't take much to kind of push them over the cliff's edge. But as far as actual drugs, there hasn't been much that has been successful,” Dove says. “I think in the end, what is going to be useful here is a molecule that will stabilize or promote the translation of myeloid transcription factors, and so you might not immediately think about this as being an immediately druggable phenomenon, but there is some evidence that by either interrupting the function of something in these cells or by stabilizing one of the myeloid transcription factors, we would be able to induce that.”

The team's findings were published in a paper titled “Reprogramming of primary human Philadelphia chromosome-positive B cell acute lymphoblastic leukemia cells into nonleukemic macrophages,” which appeared online in the Proceedings of the National Academy of Sciences on March 16.