Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor

Münch, Vera; Trentin, Luca; Herzig, Julia; Demir, Salih; Seyfried, Felix; Kraus, Johann M.; Kestler, Hans A.; Köhler, R.; Barth, Thomas F.E.; Kronnie, Geertruy te; Debatin, Klaus‐Michael; Meyer, Lüder Hinrich

doi:10.1182/blood-2017-03-769315

Cited by 67 publications

(79 citation statements)

References 66 publications

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“…4). The involvement of VEGF-A produced by leukemia cells in their CNS infiltration 56 has led several groups to propose that inhibition of VEGF production or binding is a viable therapeutic target. 24,57 We show here that BCP-ALL cells can produce a number of human cytokines in addition to VEGF-AA, including FGF2, Flt-3L, TNF-, PDGF-AA, and IL-15 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Kinjyo

Bragin²,

Grattan

et al. 2019

Journal of Leukocyte Biology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Kinjyo

Bragin²,

Grattan

et al. 2019

Journal of Leukocyte Biology

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“…Possible expression of both VEGF and VEGF‐R2 (Fig. G and H) by the leukemic blasts raises the possibility that VEGF signaling, which has been found to play a role in CNS involvement by B‐cell acute lymphoblastic leukemia, may be involved in the observed relationship between the PA and lymphoblastic infiltrate in this case …”

Section: Discussionmentioning

confidence: 68%

Co‐existent pilocytic astrocytoma with acute B‐cell leukemia within the cerebellum

et al. 2019

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Pilocytic astrocytomas are the commonest childhood brain tumor. They are typically benign and usually are solitary neoplasms. To our knowledge, only one report of a pilocytic astrocytoma with leukemia has been previously issued. We herein describe the first case with documented histopathology of a 2‐year‐old boy who had a cerebellar pilocytic astrocytoma co‐localized with an acute B‐lymphoblastic leukemia. We speculate that chemotactic migration of leukemic cells to the pilocytic astrocytoma may be partly mediated through vascular endothelial growth factor (VEGF) and VEGF receptors.

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“…Protection from leukemia relapse in the CNS is crucial to long-term survival and quality of life for leukemia patients 1–3 . One strategy for developing novel CNS-directed therapies has focused on identifying, and potentially targeting, the factors that facilitate leukemia cell trafficking to the CNS from the bone marrow 40–49 . At the same time, additional evidence suggests that the ability of leukemia cells to infiltrate the CNS is a general property of most leukemia cells and not restricted to rare clones that acquire a metastatic phenotype 14,15 .…”

Section: Discussionmentioning

confidence: 99%

Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance

Jonart

Ebadi

Basile

et al. 2019

Preprint

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word count: 200 Text word count: 3955 Abstract 1Protection from acute lymphoblastic leukemia (ALL) relapse in the central nervous system (CNS) is 2 crucial to survival and quality of life for ALL patients. Current CNS-directed therapies cause significant 3 toxicities and are only partially effective. Moreover, the impact of the CNS microenvironment on 4 leukemia biology is poorly understood. Herein, we showed that leukemia cells associated with the 5 meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced 6 chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic 7 standpoint, we identified that leukemia chemoresistance is primarily mediated by direct leukemia-8 meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, 9 we used a co-culture adhesion assay to identify drugs that disrupted leukemia-meningeal adhesion. In 1 0 addition to identifying several drugs that inhibit canonical cell adhesion targets we found that 1 1Me6TREN, a novel hematopoietic stem cell (HSC) mobilizing compound, also disrupts leukemia-1 2 meningeal adhesion in vitro and in vivo. Finally, Me6TREN enhanced the efficacy of cytarabine in 1 3 treating CNS leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a 1 4 critical influence on leukemia chemoresistance, elucidates mechanisms of CNS relapse beyond the 1 5well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for 1 6 overcoming chemoresistance. 1 7 Introduction 1 8 Central nervous system (CNS) relapse is a common cause of treatment failure among patients with 1 9 acute lymphoblastic leukemia (ALL) 1-3 . Relapses occur despite CNS-directed therapies which include 2 0 high-dose systemic chemotherapy, intrathecal chemotherapy, and cranial irradiation in some high-risk 2 1 patients. These current CNS-directed therapies are also associated with significant acute and long-2 2 3 1 mice demonstrated that all, or most, B-cell ALL clones are capable of disseminating to the CNS 14,15 . 3 2 Third, CNS leukemia relapses occur despite high dose systemic and intrathecal chemotherapy. These 3 3therapies either overcome or bypass the blood-brain barrier. Fourth, it was shown that high Mer 3 4 kinase expressing, t(1;19) leukemia cells co-cultured with CNS-derived cells exhibit G0/G1 cell cycle 3 5 arrest, suggestive of dormancy or quiescence, as well as methotrexate resistance 16 . Similarly, Akers 3 6 et al. showed that co-culture of leukemia cells with astrocytes, choroid plexus epithelial cells, or 3 7meningeal cells enhanced leukemia chemoresistance 17 . Together these observations suggest that the 3 8 pathophysiology of CNS leukemia extends beyond the role of the blood-brain barrier. We hypothesize 3 9 that the ability of leukemia cells to persist in the unique CNS niche and escape the effects of 4 0 chemotherapy and immune surveillance likely also play critical roles in CNS leukemia and relapse. 4 1 4 2 However, while extensive...

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Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor

Cited by 67 publications

References 66 publications

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

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

Co‐existent pilocytic astrocytoma with acute B‐cell leukemia within the cerebellum

Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance

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