pseudopodia to engulf particles
Investigators have reported methods for reprogramming leukemia cells into non-leukemic, macrophage-like cells.
The team reprogrammed cells derived from patients with BCR-ABL1+ precursor B-cell acute lymphoblastic leukemia (B-ALL) by exposing the cells to myeloid differentiation-promoting cytokines or by transient expression of certain transcription factors.
The group described this work in Proceedings of the National Academy of Sciences.
The research began when the investigators were trying to keep patient-derived leukemia cells alive in culture.
“We were throwing everything at them to help them survive,” said Ravindra Majeti, MD, PhD, of Stanford University School of Medicine in California.
Then, James Scott McClellan, MD, PhD, also of Stanford University School of Medicine, mentioned that some of the cells were changing shape and size, morphing into what looked like macrophages.
Dr Majeti concurred with that observation, but the reasons for the changed cells were a mystery. That is, until he remembered an old research paper, which showed that early B-cell mouse progenitor cells could be forced to become macrophages when exposed to certain transcription factors.
So he and his colleagues set out to confirm that they could transform leukemic cells into macrophage-like cells.
The team isolated CD19+CD34+ blasts from 12 adults with BCR-ABL1+ B-ALL and cultured the blasts in the presence of myeloid-differentiation-promoting cytokines. This resulted in CD14high/CD19low cells that expressed the surface markers and had the functional properties typical of normal macrophages.
The investigators also cultured B-ALL cells with the myeloid transcription factor C/EBPα or the myeloid/lymphoid transcription factor PU.1. Both factors were able to reprogram blasts into macrophage-like cells.
Experiments in mice revealed that reprogramming the blasts into macrophage-like cells eliminated their leukemogenicity.
And the investigators’ final experiments suggested that myeloid reprogramming occurs, to some degree, in humans. In samples from patients with BCR-ABL1+ B-ALL, the team found primary CD14+ monocytes/macrophages that had the BCR-ABL1+ translocation and clonally recombined VDJ regions.
Dr Majeti and his colleagues said they have reason to hope that, when the leukemic cells become macrophage-like cells, they are not only neutralized but may actually assist in fighting the leukemia.
“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,” Dr Majeti said.
