Leukemia-derived exosomes and cytokines pave the way for entry into the brain

Abstract

Infiltration of acute lymphoblastic leukemia (ALL) blasts into the CNS remains as a major clinical problem, with high risk for chemotherapy‐resistant relapse and treatment‐related morbidity. Despite the common inclusion of CNS prophylaxis treatments in therapy regimens, there are significant gaps in understanding the mechanisms that mediate leukemia cell entry into the CNS as well as roles for resident cells in the brain. In this study, we employ a xenograft model of human B cell precursor (BCP)‐ALL in immunocompromised mice. This model system recapitulates key pathological characteristics of leptomeningeal involvement seen in patients and provides insights into rare cases that involve parenchymal invasion. We examine the infiltration of engrafted leukemia blasts into brains of recipient mice and provide evidence that the interaction between blasts and brain resident cells causes aberrant activation of host cells in the brain microenvironment. BCP‐ALL blasts also release multiple cytokines and exosomes containing IL‐15 that bind and are internalized by astrocytes and brain vessel endothelial cells. Leukemic invasion is linked to production of VEGF‐AA by astrocytes and disruption of the blood‐brain‐barrier (BBB) integrity. Knockdown of either IL‐15 or IL‐15Rα in the NALM6 cell line decreases CNS infiltration in engrafted mice. These results provide important insights into the multiple mechanisms by which lymphoblasts modulate the brain microenvironment to breach the BBB for metastatic invasion.

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

“…As a counterpart concerning the blood-CNS barriers, we now describe evidence that exosomes may also modulate leukemic CNS infiltration via the BCSFB, notably, without breakdown of the BCSFB following exosome uptake. Disruption of the brain barriers was a late event in a mouse model of CNS leukemia [5], correlating to in vivo findings where parenchymal metastases occur only occasionally during early stages [4]. However, subclinical CNS infiltration in pediatric ALL at diagnosis is more frequent than previously assumed, with most of these patients presenting without neurological signs of disturbed blood-CNS barriers [26,27].…”

“…These small extracellular vesicles play a crucial role in tumor biology, and previous studies have unraveled their multifunctional role also in acute leukemias [14,15]. In this regard, Kinjyo and co-workers found an increased transmigration across human brain microvascular endothelial cells, representing the BBB, when leukemia-derived exosomes were added to their in vitro model [5]. Exosome uptake led to an upregulation of VEGF-A expression, resulting in a degradation of tight junction proteins and hence, increased permeability of the BBB.…”

“…On the other hand, most CNS relapses which occur in children are initially classified as CNS negative, indicating "undertreatment" in a subset of low-risk patients [3,4]. Therefore, predictive markers allowing to identify the personalized risk of CNS relapse more accurately are urgently warranted to further improve precise stratification of CNS directed therapy and prophylaxis in the future [5]. Identifying such markers is hampered by the fact that the nature of CNS invasion is not yet fully understood and mechanisms protecting lymphoblasts within the CNS compartment are diverse [6].…”

“…In this regard, Kinjyo and colleagues have recently described the impact of leukemia-derived exosomes on lymphoblast transmigration across the blood-brain barrier (BBB) in pediatric ALL. In their model, leukemia-derived exosomes led to modulation of astrocytes and brain microvascular endothelial cells, resulting in upregulation of vascular endothelial growth factor A (VEGF-A) expression and sequential disruption of the BBB integrity [5]. Furthermore, exosomes may well be involved in molecular mechanisms facilitating survival and chemotherapy resistance of leukemic blasts within the CNS compartment, e.g., inducing cellular quiescence [16].…”

Feasibility of tumor‑derived exosome enrichment in the onco‑hematology leukemic model of chronic myeloid leukemia

“…Emerging evidence has also suggested that membrane-bound carriers (EVs and exosomes) released by cancer cells can mediate cell-cell communication via the delivery of their contents (6). When considering leukemic cells, membrane-bound carriers can potentially alter the physiological equilibrium of extra-medullary sites (7), an interesting aspect in hematological malignancies. Innovative approaches, based on the selection of different sub-populations of tumor-associated exosomes (8), appear to be powerful and more informative than conventional isolation methods for diagnostic and prognostic purposes (9)(10)(11)(12)(13).…”