Survival has improved vastly in youngsters with acute lymphocytic leukemia (ALL). But a sure type of ALL that happens largely in infants continues to be very deadly, with a survival fee under 50 %: B-cell acute lymphoblastic leukemia with rearrangements of the combined lineage leukemia gene, or MLL B-ALL.
Something concerning the biology of one of these leukemia could be very peculiar. It can swap its mobile lineage from lymphoid to myeloid and it aggressively infiltrates the nervous system.”
Grant Rowe, MD, PhD, attending doctor, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
New work by Rowe, along with members of the Stem Cell Program and the Hematopoietic Stem Cell Transplant Program, could open a window to treating this aggressive, chemotherapy-resistant type of B-ALL.
Probing leukemia-initiating cells
Knowing that self-renewing leukemia-initiating cells spark relapse of high-risk B-ALL, Rowe and his colleagues needed to raised perceive their properties. They used single-cell RNA sequencing to see what genes these cells have been turning on at totally different factors, coupled with transplant experiments to check the cells’ proliferation. This introduced a number of key insights, revealed lately in Cell Reports (April 26).
First, leukemia-initiating cells have been extra considerable in MLL B-ALL than anticipated. Second, they may emerge not solely from immature, undifferentiated B-ALL cells, but additionally from extra mature cell populations. And third, they have been of two sorts.
“We found an enriched population of apparent leukemia-initiating cells,” says Rowe. “But these cells would change state. It turns out that they can adjust their metabolic profile to go from a stem-cell state to a non-stem-cell state, and vice versa.”
RNA profiling revealed two distinct metabolic states:
• an energetic, proliferation and progress state, marked by vitality manufacturing by means of oxidative phosphorylation
• a quieter, stem cell state, marked by low-oxygen situations and vitality manufacturing by means of glycolysis, possible reflecting a capability to stay latent, much like regular blood stem cells.
The cells’ potential to morph between these two states might clarify why they’re so arduous to focus on, and why MLL-rearranged B-ALL is so harmful, Rowe says.
Taming high-risk B-ALL aggression
The most stunning discovery was a paradox: When the researchers tried inhibiting leukemia cells within the energetic proliferation state, extra of those cells emerged, opposite to outcomes reported in different types of leukemia.
“Many therapies in adult leukemia try to target the oxidative phosphorylation state to curb growth,” says Rowe. “We thought this infant leukemia would follow that same paradigm, but we were surprised that the intervention had the opposite effect. It slowed overall proliferation, but by forcing the leukemia cells to assume a more resting state, more stem-like cells emerged and made the leukemia more aggressive.”
Conversely, Rowe and colleagues discovered that concentrating on leukemia-initiating cells of their quiet state, by inhibiting glycolysis and hypoxic signaling, curbed the leukemia. It compelled the cells again to the oxidative phosphorylation state, however they misplaced their leukemia-initiating properties within the course of.
“They don’t seem to act like stem cells any more, and don’t have the leukemia-initiating properties that seem to be related to relapse,” says Rowe. “We need to go after stem cells in this infant leukemia differently than we do in adults.”
An agenda for the longer term
Eventually, these insights might result in a brand new method to taking down this powerful most cancers. The hypoxic, glycolytic state is a method for the most cancers to lie low, nevertheless it’s additionally a vulnerability that presents a possibility.
A chemotherapy drug beforehand used for strong tumors, echinomycin, inhibits hypoxic signaling. Rowe and colleagues tried it in mice transplanted with human MLL-rearranged B-ALL. Two weeks of echinomycin remedy slowed the expansion the leukemia and depleted leukemia-initiating cells.
“We know how to dose this drug in children and its safety profiles,” says Rowe. “But our next step is to try to better understand the properties of leukemia-initiating cells, see if they’re shared in other aggressive leukemias, and better understand how to target them.”
His lab can be curious about doing related profiling of different types of ALL throughout the age spectrum.
“Hopefully we can better understand the initiating cell properties using this type of approach, and identify new vulnerabilities that could be predicted by genetics or other factors read out from the tumor.”
“Studies like these from Dr. Rowe’s lab provide deep insight into the biology of this aggressive type of childhood leukemia and may help us develop desperately needed novel therapeutic approaches,” says Scott Armstrong, MD, PhD, affiliate chief of hematology/oncology at Boston Children’s and president of Dana-Farber/Boston Children’s.
Morris, V., et al. (2022) Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells. Cell Reports. doi.org/10.1016/j.celrep.2022.110752.
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