Photo by Aaron Logan
Increasing B-cell antigen receptor (BCR) signaling beyond “a point of no return” can lead to the selective elimination of leukemic cells, according to a group of researchers.
The team knew that proximal pre-BCR signaling is toxic to Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) cells, and their experiments revealed that SYK tyrosine kinase activity mimicked constitutively active pre-BCR signaling.
So it was no surprise that pharmacologic hyperactivation of SYK prompted the removal of self-reactive B cells and selective killing of Ph+ ALL cells in vivo.
Markus Müschen, MD, PhD, of the University of California, San Francisco, and his colleagues described these findings in Nature.
When the researchers tested proximal pre-BCR signaling in mouse BCR-ABL1 cells, they found that an incremental increase of SYK activity could induce cell death.
Additional experiments showed that patient-derived Ph+ ALL cells have high levels of the inhibitory receptors PECAM1, CD300A, and LAIR1. And these receptors are needed to calibrate oncogenic signaling strength via recruitment of the inhibitory phosphatases PTPN6 and INPP5D.
So the researchers wondered if a small-molecule inhibitor of INPP5D, known as 3-a-aminocholestane (3AC), could induce SYK hyperactivation and target Ph+ ALL cells in mice.
They found that 3AC eliminated imatinib-resistant Ph+ ALL cells via rapid and massive cell death, and this significantly prolonged survival in the mice.
Dr Müschen and his colleagues noted that only Ph+ ALL cells were marked for destruction, which suggests a BCR-targeted drug could overcome imatinib resistance without affecting normal B cells.
The team also pointed out that a short exposure to 3AC was sufficient to commit the leukemia cells to death and to clear most of the disease burden from mice.
Dr Müschen said 3AC’s fast action was encouraging, because it remains unknown whether prolonged BCR hyperactivation is safe. That is why he and his colleagues are now focusing on formulating hyperactivating drugs that could be administered for only a few hours.
“These experiments show that we can engage signaling checkpoints in a very short period of time and that, once these checkpoints are engaged, the cell is irreversibly slated for death; it’s a point of no return,” Dr Müschen said.
“The next step is to work with medicinal chemists to make better ALL drugs that will overstimulate the B-cell receptor pathway and . . . could be used on a treatment schedule to elicit a very strong, but time-limited, spike in signaling to engage negative B-cell selection.”
