After a chance observation in the lab, … researchers found a method that can cause dangerous leukemia cells to mature into harmless immune cells known as macrophages. The findings are described in a paper that published online March 16 in the Proceedings of the National Academy of Sciences.
B-cell acute lymphoblastic leukemia with a mutation called the Philadelphia chromosome is a particularly aggressive cancer with poor outcomes, said Ravi Majeti, MD, PhD, an assistant professor of medicine and senior author of the paper. So finding potential treatments is particularly exciting.
Majeti and his colleagues made the key observation after collecting leukemia cells from a patient and trying to keep the cells alive in a culture plate. “We were throwing everything at them to help them survive,” said Majeti, who is also a member of the Stanford Cancer Institute and the Stanford Institute for Stem Cell Biology and Regenerative Medicine.
Postdoctoral scholar Scott McClellan MD, PhD, a lead author of the paper, mentioned that some of the cancer cells in culture were changing shape and size into what looked like macrophages. Majeti concurred with that observation, but the reasons for the changed cells were a mystery 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 — proteins that bind to certain DNA sequences.
“B-cell leukemia cells are in many ways progenitor cells that are forced to stay in an immature state,” Majeti said. So he, McClellan and student Christopher Dove, an MD/PhD student and the paper’s other lead author, did more experiments and confirmed that methods shown to have altered the fate of the mouse progenitor cells years ago could be used to transform these human cancer cells into macrophages, which can engulf and digest cancer cells and pathogens.
Majeti and his colleagues have some reason to hope that when the cancer cells become macrophages they will not only be neutralized, but may actually assist in fighting the cancer. Like a bloodhound owner who gives the dog a sniff of an object that was associated with the person or animal he wants to track, macrophage cells present recognizable bits of abnormal cells to other immune cells so that they can launch an attack. “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.The researchers’ next steps will be to see if they can find a drug that will prompt the same reaction and that could serve as the basis for a therapy for the leukemia. There is some precedent for such a treatment. Retinoic acid is commonly used to treat another cancer called acute promyelocytic leukemia. In that case, retinoic acid is used to turn cancer cells into mature cells called granulocytes. This treatment is the only well-established therapy that matures, or “differentiates,” cancer cells, but researchers around the world are hopeful of finding many more. “There’s big-time interest in differentiation therapies for cancer,” Majeti said. …
Retinoic acid is responsible for most of the activity of vitamin A. The abstract has more details that the process was achieved with myeloid differentiation-promoting cytokines.
BCR–ABL1+ precursor B-cell acute lymphoblastic leukemia (BCR–ABL1+ B-ALL) is an aggressive hematopoietic neoplasm characterized by a block in differentiation due in part to the somatic loss of transcription factors required for B-cell development. We hypothesized that overcoming this differentiation block by forcing cells to reprogram to the myeloid lineage would reduce the leukemogenicity of these cells. We found that primary human BCR–ABL1+ B-ALL cells could be induced to reprogram into macrophage-like cells by exposure to myeloid differentiation-promoting cytokines in vitro or by transient expression of the myeloid transcription factor C/EBPα or PU.1. The resultant cells were clonally related to the primary leukemic blasts but resembled normal macrophages in appearance, immunophenotype, gene expression, and function. Most importantly, these macrophage-like cells were unable to establish disease in xenograft hosts, indicating that lineage reprogramming eliminates the leukemogenicity of BCR–ABL1+ B-ALL cells, and suggesting a previously unidentified therapeutic strategy for this disease.
Here’s a bit more about cytokines:
Cytokines exist in peptide, protein and glycoprotein (proteins with a sugar attached) forms. The cytokines are a large family of molecules that are classified in various different ways due to an absence of a unified classification system.
Examples of cytokines include the agents interleukin and the interferon which are involved in regulating the immune system’s response to inflammation and infection.
There is debate among experts over whether certain molecules should be called hormones or cytokines. Classic proteins, for example, have been understood to circulate in nanomolar concentrations and not to differ by more than one order of magnitude. Cytokines, however, circulate in picomolar concentrations and may increase in magnitude almost a thousand-fold in response to an infection or inflammation.
In addition, cytokines have a much larger distribution of sources for their production, with nearly all cells that have a nucleus capable of producing interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α), particularly endothelial cells, epithelial cells and resident macrophages. The classic hormones, on the other hand, are secreted from discrete glands such as the pancreas which secretes insulin.