Survival has greatly improved in children with acute lymphocytic leukemia (ALL). But some form of ALL that occurs primarily in infants is still very lethal, with a survival rate below 50%: acute B-cell lymphoblastic leukemia with rearrangements of the mixed-lineage leukemia gene, or MLL B-ALL.
Something about the biology of this type of leukemia is very peculiar. It can change its cell line from lymphoid to myeloid and aggressively infiltrate the nervous system. “
Grant Rowe, MD, PhD, Assistant Physician, Dana-Farber / Boston Children’s Cancer and Blood Disorders Center
Rowe’s new work, along with members of the stem cell program and the hematopoietic stem cell transplant program, may open a window to treat this aggressive and resistant form of B-ALL chemotherapy.
Leukemia-initiating cell screening
Knowing that cells that initiate self-renewing leukemia cause a relapse of high-risk B-ALL, Rowe and colleagues wanted to better understand its properties. They used unicellular RNA sequencing to see which genes were activating these cells at different points, along with transplant experiments to study cell proliferation. This provided several key ideas, recently published in Cell Reports (April 26).
First, leukemia-initiating cells were more abundant in MLL B-ALL than expected. Second, they could arise not only from immature and undifferentiated B-ALL cells, but also from more mature cell populations. And third, they were of two kinds.
“We found an enriched population of apparent leukemia-initiating cells,” says Rowe. “But these cells would change state. It turns out they can adjust their metabolic profile to go from a stem cell state to a non-stem cell state, and vice versa.”
The RNA profile revealed two different metabolic states:
• an active state of proliferation and growth, marked by the production of energy through oxidative phosphorylation. • A state of calmer stem cells, marked by low oxygen conditions and energy production through glycolysis, which probably reflects the ability to remain latent, similar to normal blood stem cells. .
The ability of cells to transform between these two states could explain why they are so difficult to target and why B-ALL reordered with MLL is so dangerous, Rowe says.
Taming the high-risk aggressiveness of B-ALL
The most surprising finding was a paradox: when researchers tried to inhibit leukemia cells in a state of active proliferation, more of these cells emerged, contrary to the results reported in other forms of leukemia.
“Many therapies in adult leukemia try to target the oxidative phosphorylation state to slow growth,” says Rowe. “We thought that this childhood leukemia would follow the same paradigm, but we were surprised that the intervention had the opposite effect. It slowed the general proliferation, but by forcing the leukemia cells to take on a more rested state, they arose making leukemia-like stem cells more aggressive. “
In contrast, Rowe and colleagues found that targeting leukemia-inducing cells in their calm state, inhibiting glycolysis and hypoxic signaling, slowed leukemia. It forced the cells to return to the oxidative phosphorylation state, but they lost their leukemia-initiating properties in the process.
“They no longer appear to act as stem cells and do not have the leukemia-initiating properties that appear to be related to relapse,” says Rowe. “We have to go after stem cells in this childhood leukemia in a different way than in adults.”
An agenda for the future
Eventually, these ideas could lead to a new approach to eliminating this harsh cancer. The hypoxic and glycolytic state is a way for cancer to be low, but it is also a vulnerability that presents an opportunity.
A chemotherapy drug previously used for solid tumors, echinomycin, inhibits hypoxic signaling. Rowe and colleagues tested it on mice transplanted with B-ALL rearranged with human MLL. Two weeks of equinomycin treatment slowed the growth of leukemia and depleted the leukemia-initiating cells.
“We know how to dose this drug in children and their safety profiles,” says Rowe. “But our next step is to try to better understand the properties of leukemia-initiating cells, see if they share with other aggressive leukemias, and better understand how to target them.”
His lab is also interested in making a similar profile of other forms of ALL across the age spectrum.
“We hope we can better understand the properties of early cells through this type of approach and identify new vulnerabilities that could be predicted by genetics or other read-off tumor factors.”
“Studies like these in Dr. Rowe’s lab provide an in-depth insight into the biology of this aggressive type of childhood leukemia and can help us develop new therapeutic approaches that they desperately need,” says Scott Armstrong, MD, PhD. Boston Hematology / Oncology. Infantile and president of Dana-Farber / Boston Children’s.
Source:
Boston Children’s Hospital
Magazine reference:
Morris, V., et al. (2022) Hypoxic glycolytic metabolism is a vulnerability of cells initiating acute lymphoblastic leukemia B. Cell reports. doi.org/10.1016/j.celrep.2022.110752.