The central nervous system microenvironment influences the leukemia transcriptome and enhances leukemia chemo-resistance

Gaynes, Jeffrey S.; Jonart, Leslie M.; Zamora, Edward A.; Naumann, Jordan A.; Gossai, Nathan; Gordon, Peter M.

doi:10.3324/haematol.2016.152926

Cited by 29 publications

(33 citation statements)

References 14 publications

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“…The HCN-2 neuronal cell line was obtained from ATCC. Leukemia cells expressing green fluorescent protein (GFP) were generated as described 20 . Murine leukemia cells, generated by BCR/ABL p190 expression in hematopoietic cells from CD45.1 Arf -/mice [21][22][23] , were provided by Dr. Michael Farrar (University of Minnesota).…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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

et al. 2019

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“…As a result, we focused our work on the meninges. However, it is certainly possible, and perhaps even likely, that other cells or tissues within the CNS, such as the choroid plexus, may also impact leukemia biology 17,20 . This may be analogous to the bone marrow microenvironment in which distinct niches (endosteal, vascular) exert unique effects on hematopoietic stem and leukemia cells 50 .…”

Section: Discussionmentioning

confidence: 99%

“…The HCN-2 neuronal cell line was obtained from ATCC. Leukemia cells expressing green fluorescent protein (GFP) were generated as described 20 . Murine leukemia cells, generated by BCR/ABL p190 expression in hematopoietic cells from CD45.1 Arf -/- mice 21–23 , were provided by Dr. Michael Farrar (University of Minnesota).…”

Section: Methodsmentioning

confidence: 99%

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

Jonart

Ebadi

Basile

et al. 2019

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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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“…It has also long been known that CNS ALL is predominantly a leptomeningeal disease (Price & Johnson, ), a fact that has often been interpreted as reflecting mechanisms of CNS invasion (Williams et al , ; Münch et al , ; Yao et al , ). However, it is becoming clear that factors promoting ALL survival and chemoresistance once it has entered the CNS are probably more important than mechanisms of entry into the CNS (Akers et al , ; Krause et al , ; Gaynes et al , ), suggesting that a biologically and clinically significant bona fide CNS niche exists for ALL. Niches are, by definition, complex functional support structures that provide myriad inputs to support the growth and survival of particular cell types.…”

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confidence: 99%

“…The extracellular matrix protein laminin appears to be required for entry of lymphoblasts into the CNS (Yao et al , ). After entry, several CNS stromal cell types are capable of supporting and promoting ALL survival (Akers et al , ; Gaynes et al , ); this is partly through the expression of membrane proteins such as vascular cell adhesion protein 1 (VCAM1) (Hall et al , ) and the elaboration of soluble factors such as interleukins 15 (IL‐15) and 7 (IL‐7) (Lee et al , ; Michaelson et al , ). In addition to serving as ALL growth and survival factors, both IL‐15 and IL‐7 expression also predict CNS involvement (Williams et al , ; Alsadeq et al , ).…”

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confidence: 99%

ALL the comforts of homing: lymphoblasts find cerebrospinal fluid inhospitable without meningeal cell contact

Manousopoulou

Wang

2020

Br J Haematol

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The central nervous system microenvironment influences the leukemia transcriptome and enhances leukemia chemo-resistance

Cited by 29 publications

References 14 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

ALL the comforts of homing: lymphoblasts find cerebrospinal fluid inhospitable without meningeal cell contact

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