Micrograph showing ALL
Researchers believe they have solved the mystery of how acute lymphoblastic leukemia (ALL) infiltrates the central nervous system (CNS).
Experiments in mice suggested that ALL enters the CNS not by breaching the blood-brain barrier but by evading it.
The researchers said they found that expression of the laminin receptor α6 integrin, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.
“It’s a very unexpected way for cells to travel into the central nervous system,” said Dorothy Sipkins, MD, PhD, of Duke University in Durham, North Carolina.
She and her colleagues described the cells’ journey in Nature.
The researchers said they found that α6 integrin–laminin interactions mediate the migration of ALL cells toward the cerebrospinal fluid.
The team noted that α6 integrin is expressed in most cases of ALL, and laminin surrounds blood vessels that pass directly through the vertebrae to the meninges tissue that lines the spinal cord and brain.
Experiments indicated that ALL cells latch onto the laminin surrounding these blood vessels and travel down into the meninges region where cerebral spinal fluid circulates.
“Understanding how ALL gets into the central nervous system arms us with new ways to target this pathway and hopefully shut it down,” Dr Sipkins noted.
She and her colleagues found that treatment with a PI3Kδ inhibitor may be one way to do that.
The team tested the PI3Kδ inhibitor GS-649443 in a mouse model of CNS ALL (Nalm-6) and found the drug decreased α6 integrin expression on ALL cells.
Mice treated with the inhibitor had a 50% decrease in CNS disease burden compared to vehicle-treated controls. However, there was no significant difference between treated mice and controls when it came to bone marrow or splenic Nalm-6 disease burden or peripheral blood cell counts.
The researchers observed similar results in another model of CNS disease (RCH-ACV ALL).
The team also tested α6 integrin-neutralizing antibodies in Nalm-6-engrafted mice. There was no difference in peripheral disease burden between targeted and isotype control antibody-treated mice. However, anti-α6 integrin-treated mice had a reduction in cerebrospinal fluid blast counts.
This research was supported by the Duke Cancer Institute and Gilead Sciences, Inc., which provided the PI3Kδ inhibitor.