(blue and purple) invaded
by leukemia cells (yellow).
Image courtesy of Edwin
Hawkins, Delfim Duarte,
and Imperial College London
Preclinical research has shed light on how certain leukemia cells survive treatment and could pave the way for better therapeutic targeting of these resistant cells.
Researchers have speculated that some leukemia cells survive treatment by hiding out in specific niches in the bone marrow.
Results of the new research, conducted in mouse models and human samples of T-cell acute lymphoblastic leukemia (T-ALL), contradict that theory.
The experiments showed that resistant T-ALL cells move rapidly through the bone marrow before, during, and after treatment, interacting with—and sometimes killing—healthy cells.
“We expected the cells that survived treatment to be sat in particular niches, but, instead, they are very active throughout the bone marrow,” said Cristina Lo Celso, PhD, of Imperial College London in the UK.
“We now know that it would be ineffective to target particular niches in the bone marrow to tackle treatment-resistant leukemia. Now that we know that the cells don’t hide, we can explore why that is and how their movement helps them to survive. Ultimately, we want to find out whether we can stop the movement and whether this could kill the treatment-resistant cells.”
Dr Lo Celso and her colleagues described these findings in a letter to Nature.
The researchers used intravital microscopy to track the movement of T-ALL cells in mice—before, during, and after treatment. Treatment consisted of dexamethasone alone, vincristine alone, or combination dexamethasone, vincristine, and L-asparaginase.
The team found that T-ALL cells moved around rapidly, not showing any preference for bone marrow subcompartments. The cells’ behavior was consistent over time—from the earliest bone marrow seeding through to treatment response and resistance.
However, the researchers noted that surviving T-ALL cells were “highly migratory” and travelled at significantly faster speeds than early infiltrating cells. In addition, resistant T-ALL cells were still capable of undergoing division at times when other T-ALL cells were dying.
The team suggested that the act of moving may help T-ALL cells to survive, possibly through short-lived interactions with other cells.
This theory was supported by the discovery that T-ALL cells actively attack osteoblasts. The researchers noted that osteoblasts are associated with hematopoietic fitness. So the loss of osteoblasts may contribute to the loss of healthy hematopoiesis observed in leukemia patients.
The team believes this insight could aid the development of treatments to safeguard the production of healthy blood cells in T-ALL patients.
“Our study supports the idea that, at least in this leukemia, new therapies should target the cancer cells themselves instead of the surrounding normal stromal cells to better eradicate the disease,” said study author Delfim Duarte, MD, a PhD student at Imperial College London.
“Our work also suggests that protecting normal stromal bone cells from the attack of leukemia cells can have wide implications in the support of healthy blood cell production,” said Edwin Hawkins, PhD, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“Keeping blood cell levels up would prevent anemia, infection, and bleeding.”
