Project Details
Description
ABSTRACT
Central nervous system (CNS) relapse is a major cause of treatment failure among patients with acute
lymphoblastic leukemia (ALL). Notably, isolated CNS relapse occurs in ~3-8% of children with ALL and
accounts for 30–40% of initial relapses in some clinical trials. Furthermore, current CNS-directed therapies are
associated with significant toxicities. As a result, novel CNS-directed leukemia therapies are urgently needed
to improve long-term outcomes while decreasing treatment-related morbidity. Although extensive research has
demonstrated a critical role of the bone marrow microenvironment in leukemia biology, the impact of the CNS
microenvironment on leukemia cell survival and chemoresistance is largely unknown. We developed a novel
ex vivo co-culture system and an in vivo xenotransplantation approach to investigate the effects of the CNS
niche on leukemia biology and chemoresistance. We then used these model systems to identify that 1)
leukemia cells cultured in cerebral spinal fluid (CSF) in vitro and in vivo have diminished survival relative to
serum or media, 2) leukemia cells predominantly localize to the meninges within the CNS, and 3) leukemia
cells co-cultured with meningeal cells, or associated with the meninges of mice, exhibit enhanced survival and
chemoresistance. We then identified that direct meningeal-leukemia interactions promote leukemia cell survival
by modulating apoptosis balance, cell cycle progression, and quiescence. Importantly, leukemia
chemoresistance was reversible and overcome by detaching the leukemia cells from the meninges. We then
used a co-culture adhesion assay to identify drugs that disrupt the interaction between leukemia and
meningeal cells. In addition to identifying several drugs that inhibit canonical cell adhesion targets and
pathways, including the CXCR4 antagonist AMD3100, we found that Me6TREN, a novel small-molecule
hematopoietic stem cell (HSC) mobilizing compound, also disrupts the interaction between leukemia and
meningeal cells. This work demonstrates that the meninges exert a unique and critical influence on leukemia
chemoresistance and defines novel mechanisms of CNS relapse beyond the well-described role of the blood-
brain barrier. Based on this work, our central hypothesis is that the leukemia-meningeal cell interaction is a
critical regulator of leukemia cell survival and chemoresistance in the CNS. Moreover, from a therapeutic
standpoint, we hypothesize that niche disruption may be more efficacious in the CNS than in the bone marrow
because of the less supportive environment of the CSF relative to the blood or serum. The objectives in this
proposal are to use our in vitro and in vivo model systems for CNS leukemia to dissect the molecular
mechanisms that mediate leukemia adhesion (Aim 1) and chemoresistance (Aim 2) in the CNS and test novel,
clinically translatable therapies for CNS leukemia including Me6TREN and AMD3100 (Aim 3).
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Status | Active |
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Effective start/end date | 3/4/20 → 2/28/25 |
Funding
- National Cancer Institute: $352,275.00
- National Cancer Institute: $317,048.00
- National Cancer Institute: $345,230.00
- National Cancer Institute: $352,275.00
- National Cancer Institute: $317,048.00
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