Bone marrow microenvironment modulation of acute lymphoblastic leukemia phenotype

Moses, Blake S.; Slone, William L.; Thomas, Patrick; Evans, Rebecca; Piktel, Debbie; Angel, Peggi; Walsh, Callee M.; Cantrell, Pamela S.; Rellick, Stephanie L.; Martin, Karen H.; Simpkins, James W.; Gibson, Laura F.

doi:10.1016/j.exphem.2015.09.003

Cited by 32 publications

(47 citation statements)

References 42 publications

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“…We demonstrate that p27 is abundant in the leukemic cells influenced by the BMM (Fig. 2D) consistent with previous observations of BMM supported ALL quiescence (17). …”

Section: Discussionsupporting

confidence: 92%

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Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia

Moses

Evans

Slone

et al. 2016

Molecular Cancer Research

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Acute lymphoblastic leukemia (ALL) has many features in common with normal B-cell progenitors, including their ability to respond to diverse signals from the bone marrow microenvironment (BMM) resulting in regulation of cell cycle progression and survival. Bone marrow derived cues influence many elements of both steady state hematopoiesis and hematopoietic tumor cell phenotypes through modulation of gene expression. MicroRNAs (miRNAs) are one regulatory class of small non-coding RNAs that have been shown to be increasingly important in diverse settings of malignancy. In the current study, miRNA profiles were globally altered in ALL cells following exposure to primary human bone marrow niche cells including bone marrow stromal cells (BMSC) and primary human osteoblasts (HOB). Specifically, mature miR-221 and miR-222 transcripts were decreased in ALL cells co-cultured with BMSC or HOB, coincident with increased p27 (CDKN1B), a previously validated target. Increased p27 protein in ALL cells exposed to BMSC or HOB is consistent with accumulation of tumor cells in the G0-phase of the cell cycle and resistance to chemotherapy induced death. Overexpression of miR-221 in ALL cells during BMSC or HOB co-culture prompted cell cycle progression and sensitization of ALL cells to cytotoxic agents, blunting the protective influence of the BMM. These novel observations indicate that BMM regulation of miR-221/222 contributes to marrow niche supported tumor cell quiescence and survival of residual cells. Implications Niche influenced miR-221/222 may define a novel therapeutic target in ALL to be combined with existing cytotoxic agents to more effectively eradicate refractory disease that contributes to relapse.

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“…We demonstrate that p27 is abundant in the leukemic cells influenced by the BMM (Fig. 2D) consistent with previous observations of BMM supported ALL quiescence (17). …”

Section: Discussionsupporting

confidence: 92%

“…Our lab has previously shown ALL cells associated with the bone marrow microenvironment (BMM) have altered cell cycle kinetics coincident with protection from several conventional chemotherapeutic agents (17). Two miRNAs described to regulate leukemic cell proliferation are miR-221 and miR-222 (18).…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia

Moses

Evans

Slone

et al. 2016

Molecular Cancer Research

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“…This result supports a model in which leukemia chemoresistance is primarily dependent upon direct interactions between the leukemia and meningeal cells with smaller contributions from a soluble factor(s) secreted by the meningeal cells. Together these results further support that the pathophysiology of CNS leukemia and relapse is more complex than simply the ability of leukemia cells or chemotherapy to access the restricted CNS microenvironment and complement other extensive lab and clinical data demonstrating that cell-autonomous factors play an essential role in leukemia biology 50,53,54 .…”

Section: Discussionsupporting

confidence: 71%

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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“…As previously mentioned, the bone marrow microenvironment plays a pivotal role in the development of chemoprotection in ALL by inducing survival pathways in ALL cells [15]. For example, we showed earlier that osteoblasts can protect ALL cells from cell death induced by treatment with chemotherapeutic drugs dexamethasone and vincristine [8].…”

Section: Resultsmentioning

confidence: 99%

Epigenetic drug combination overcomes osteoblast-induced chemoprotection in pediatric acute lymphoid leukemia

2017

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Although there has been much progress in the treatment of acute lymphoblastic leukemia (ALL), decreased sensitivity to chemotherapy remains a significant issue. Recent studies have shown how interactions with the bone marrow microenvironment can protect ALL cells from chemotherapy and allow for the persistence of the disease. Epigenetic drugs have been used for the treatment of ALL, but there are no reports on whether these drugs can overcome bone marrow-induced chemoprotection. Our study investigates the ability of the DNA methyltransferase inhibitor azacitidine and the histone deacetylase inhibitor panobinostat to overcome chemoprotective effects mediated by osteoblasts. We show that the combination of azacitidine and panobinostat has a synergistic killing effect and that this combination is more effective than cytarabine in inducing ALL cell death in co-culture with osteoblasts. We also show that this combination can be used to sensitize ALL cells to chemotherapeutics in the presence of osteoblasts. Finally, we demonstrate that these effects can be replicated ex vivo in a number of mouse passaged xenograft lines from both B-ALL and T-ALL patients with varying cytogenetics. Thus, our data provides evidence that azacitidine and panobinostat can successfully overcome osteoblast-induced chemoprotection in vitro and ex vivo in both B-ALL and T-ALL cells.

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Bone marrow microenvironment modulation of acute lymphoblastic leukemia phenotype

Cited by 32 publications

References 42 publications

Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia

Bone Marrow Microenvironment Niche Regulates miR-221/222 in Acute Lymphoblastic Leukemia

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

Epigenetic drug combination overcomes osteoblast-induced chemoprotection in pediatric acute lymphoid leukemia

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