Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: Reconciling biological concepts and clinical issues

Gaudichon, Jérémie; Jakobczyk, Hélène; Debaize, Lydie; Cousin, Élie; Galibert, Marie‐Dominique; Troadec, Marie‐Bérengère; Gandemer, Virginie

doi:10.1016/j.blre.2019.04.003

Cited by 62 publications

(75 citation statements)

References 242 publications

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“… 55 As many of these adhesion pathways contribute to the bone marrow leukemia niche, Me6TREN may also diminish leukemia chemoresistance in other leukemia niches. 53 , 56 This possibility is potentially supported by our data demonstrating that Me6TREN extended the overall survival of mice treated with cytarabine. However, if upon further testing Me6TREN only disrupts leukemia-meningeal adhesion and the effect on survival is due only to decreased CNS leukemia progression, Me6TREN could still be effective in treating isolated CNS relapses, for use in upfront therapy to reduce the risk of CNS relapse, or potentially to reduce the dose or intensity of current CNS-directed therapies that carry significant risks of short- and long-term toxicity.…”

Section: Discussionmentioning

confidence: 66%

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

et al. 2019

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word count: 200 Text word count: 3820Abstract Protection from acute lymphoblastic leukemia relapse in the central nervous system is crucial to survival and quality of life for leukemia patients. Current central nervous system directed therapies cause significant toxicities and are only partially effective. Moreover, the impact of the central nervous system microenvironment on leukemia biology is poorly understood. Herein, we showed that leukemia cells associated with the meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic standpoint, we identified that leukemia chemoresistance is primarily mediated by direct leukemia-meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, we used a co-culture adhesion assay to identify drugs that disrupted leukemiameningeal adhesion. In addition to identifying several drugs that inhibit canonical cell adhesion targets we found that Me6TREN (Tris[2-(dimethylamino)ethyl]amine), a novel hematopoietic stem cell mobilizing compound, also disrupted leukemia-meningeal adhesion and enhanced the efficacy of cytarabine in treating central nervous system leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a critical influence on leukemia chemoresistance, elucidates mechanisms of relapse beyond the well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance. leukemia cells. Experiments were then performed 3-5 weeks after injection. In general, after euthanasia the mice were cardiac perfused with PBS, meninges or other tissues removed using a dissecting microscope, and dissociated by gently washing through a 0.40 µm filter (Millipore). Cells were then stained with fluorescent antibodies against CD19 (NALM-6; eBioscience) or CD3 (Jurkat, eBioscience) and assessed for apoptosis or cell cycle as described. Alternatively, leukemia cells could be purified from meningeal cells using immunomagnetic separation and either CD19 or CD3 antibodies (Stem Cell Technologies or Miltenyi Biotec) and placed back into suspension. In drug treatment experiments, Me6TREN 10 mg/kg and cytarabine 50 mg/kg were given by subcutaneous and intraperitoneal injection, respectively. Cerebral spinal fluid (CSF) was obtained from mice as described 25 . Briefly, mice were euthanized and a scalp incision was made at the midline to expose the dura mater overlying the cisterna magna. Under a dissection microscope, a tapered, pulled glass capillary tube was then inserted through the dura and into the cisterna magna to obtain clear cerebral spinal fluid (CSF). Experiments with murine leukemia cells (BCR/ABL p190 expression in hematopoietic cells from Arf -/mice; CD45.1 background) used C57BL/6 mice. In these experiments, ~3000 leukemia cells/mouse were injected via the tail vein. Statistical analysis:Results are shown as the mean plus or minus the SEM of the results of at...

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Section: Discussionmentioning

confidence: 66%

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

et al. 2019

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“…However, Me6TREN mobilizes mouse hematopoietic stem/progenitor cells from the bone marrow through effects on several cell adhesion and migration pathways including MMP-9, SDF-1/CXCR4, and VECAM/VLA-4 25 . As these adhesion pathways also contribute to the bone marrow leukemia niche, it is possible that Me6TREN may exhibit efficacy in other leukemia niches 53,55 . However, if upon further testing Me6TREN only disrupts leukemia-meningeal adhesion, Me6TREN could still be effective in treating isolated CNS relapses or for use in upfront therapy to reduce the risk for CNS relapse.…”

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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“…Extramedullary relapse, which is not a frequent recurrence of leukemia occurring in sites other than the bone marrow, is an important cause of treatment failure among patients with acute lymphoblastic leukemia (ALL) [1]. One-third of all extramedullary ALL relapses are reported in the central nervous system [2], while the relapses in testicle and skin are relatively uncommon [3,4].…”

Section: Introductionmentioning

confidence: 99%

Successful treatment of acute B lymphoblastic leukemia relapse in the skin and testicle by anti-CD19 CAR-T with IL-6 knocking down: a case report

et al. 2020

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Background: Extramedullary relapse is an important cause of treatment failure among patients with acute lymphoblastic leukemia (ALL). This type of relapse is commonly observed in the central nervous system, while it is rare in the testicles and skin. Chimeric antigen receptor-modified T cell (CAR-T) therapy targeting CD19 has shown to be a beneficial treatment approach for relapsed/refractory B cell acute lymphoblasticleukemia (r/r BALL). Yet, few studies have reported data regarding the treatment of extramedullary BALL relapse, especially both in skin and testicle, with CART therapy. Case presentation: Here we reported a single case of a patient with relapsed BALL in skin and testicle who was successfully treated by the shRNA-IL6-modified anti-CD19 CAR-T(ssCAR-T-19) therapy. A 29-year-old man with relapsed BALL in skin and testicle was enrolled in clinal trial involving the shRNA-IL6-modified anti-CD19 CAR-T(ssCAR-T-19) therapy (ClinicalTrials.gov number, NCT03919240). The patient had toxicity consistent with the grade 1 cytokine release syndrome. Conclusions: ssCART-19 therapy may be used to effectively eliminate infiltrating leukemia cells in the skin and testicle with mild toxicity, which could be a much safer approach to bridge allo-HSCT, thus further improving the patient's outcome.

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Mechanisms of extramedullary relapse in acute lymphoblastic leukemia: Reconciling biological concepts and clinical issues

Cited by 62 publications

References 242 publications

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

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

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

Successful treatment of acute B lymphoblastic leukemia relapse in the skin and testicle by anti-CD19 CAR-T with IL-6 knocking down: a case report

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