Colonization of subventricular neurogenic niche by leukemia cells prevents the formation of new neurons

The subventricular neurogenic niche is a region of the brain where tumor cells can hide from chemotherapy treatment to reappear later, causing relapses in patients with childhood acute lymphoblastic leukemia (ALL), and preventing the formation of new neurons, as demonstrated by research led by Universidad Complutense de Madrid (UCM).

Although over recent decades childhood ALL survival rates have improved, between 10 and 15% of patients suffer a relapse despite their treatment. A third of these relapses are caused by the "hiding places" that the tumor cells find within the Central Nervous System (CNS).

The subventricular neurogenic niche, which is one of the few places in the brain where new neurons are generated over the course of our life, apparently constitutes a new refuge for leukemia cells."

Ángeles Vicente, Director of the UCM Stem Cell, Immunity and Cancer Research Group

The subventricular neurogenic niche is one of the few parts of the brain where new neuron generation (neurogenesis) continues. As a result of being colonized by the leukemia cells, inducing an inflammatory environment in the niche, this capacity is altered.

Study in mice transplanted with human leukemia cells

The paper, published in Haematologica, used a xenogeneic animal model: immunodeficient mice transplanted with human childhood ALL leukemia cells to recreate the disease. Previous studies with the same group had already identified another zone of the CNS where cells were evading treatment - the choroid plexus stroma.

This study demonstrates the consequences of ALL in pediatric patients whose CNS is at the developmental stage. Although most neurons are generated before birth, new cells are constantly generated in specific areas of the brain, from where they migrate to various regions of the prefrontal cortex, essentially during the early years of life.

"As a result, alterations in the formation of these neurons and their subsequent incorporation within the neuronal circuits of the developing brain could in part be responsible for the cognitive, sensory and motor alterations observed in ALL survivors, previously attributed solely to the side effects of the chemotherapy", underlines the lead author of the UCM research paper, Lidia M Fernández-Sevilla.

The study was conducted using both histological and flow cytometry techniques to locate leukemia cells in the subventricular neurogenic niche zone, as well as the subsequent analysis of the cell populations in the niche. In parallel, in vitro tests were performed to analyze the effects of leukemia on the neural precursors.

Aside from the UCM, the study also involves the University of Valencia, the Niño Jesús Children's University Hospital and the San Carlos Clinical Hospital Health Research Institute in Madrid.

Source:
Journal reference:

Fernández-Sevilla, L.M., et al. (2022) Acute lymphoblastic leukemia cells are able to infiltrate the brain subventricular zone stem cell niche and impair neurogenesis. Haematologica. doi.org/10.3324/haematol.2021.279383.

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