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

Moses, Blake S.; Evans, Rebecca; Slone, William L.; Piktel, Debbie; Martínez, Iván; Craig, Michael; Gibson, Laura F.

doi:10.1158/1541-7786.mcr-15-0474

Cited by 32 publications

(25 citation statements)

References 50 publications

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“…The leukemic cells which were buried under the BMSC were separated by size exclusion with G10 sephadex after vigorous washing to remove all leukemic cells adhered to the top of the BMSC [9]. Buried leukemic cells were designated phase dim cells (PD) and have been previously described to be the most chemotherapy-resistant population [11, 12]. As such, they are not assumed to be identical, but rather are used as a model, for refractory tumor cells that are known to be clinically problematic in the treatment of ALL.…”

Section: Methodsmentioning

confidence: 99%

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

Nair

Piktel

Thomas

et al. 2019

Preprint

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Tel. (304) 293-7206 21 22 Keywords: B-cell acute lymphoblastic leukemia, mitochondrial respiration, pyrvinium 23 pamoate, drug resistance, nanoparticles, co-culture model. 24 225 Abstract Reprogramming of cellular pathways is a crucial mechanism of drug resistance 26 and survival in refractory acute lymphoblastic leukemia (ALL) cells. In the present study, 27 we performed an unbiased gene expression analysis and identified a dysfunctional 28 mitochondrial respiration program in drug-resistant ALL cells grown in a co-culture system 29 with bone marrow stromal cells (BMSC). Specifically, the activity of the complexes within 30 the electron transport chain was significantly downregulated, correlated with decreased 31 mitochondrial mass and ATP production in drug-resistant ALL cells. To validate 32 mitochondrial respiration as a druggable target, we utilized pyrvinium pamoate (PP), a 33 known inhibitor of mitochondrial respiration and documented its anti-leukemic activity in 34 several ALL cell lines grown alone or in co-culture with BMSC. To increase the 35 bioavailability profile of PP, we successfully encapsulated PP in a nanoparticle drug 36 delivery system and demonstrated that it retained its anti-leukemic activity in a 37 hemosphere assay. PP anti-leukemic activity was decreased by the addition of sodium 38 pyruvate, and furthermore, PP was found to have an additive anti-leukemic effect when 39 used in combination with rotenone, a mitochondrial complex I inhibitor with activity similar 40 to PP on the mitochondrial respiration. Importantly, PP's cell death activity was found to 41 be specific for leukemic cells as primary normal immune cells were resistant to PP-42 mediated cell death. In conclusion, we have demonstrated that PP is a novel therapeutic 43 lead compound that counteracts the respiratory reprogramming found in refractory ALL 44 cells. 45 46 47 3 48 Introduction 49 B lineage acute lymphoblastic leukemia (ALL) originates from differentiation arrest 50 followed by uncontrolled proliferation of the immature B lymphoid cells, resulting in 51 accumulation within the bone marrow (BM) [1]. This rapid accumulation of the leukemic 52 blast cells leads to the "hijacking" of the BM niche and the impairment of steady state 53 hematopoiesis. Thus, coincident with progression of disease, there is a collapse of the 54 functional integrity of the hematopoietic system [2]. The drivers of the disease have not 55 yet been fully elucidated, but are known to include changes in chromosomal number 56 (hyperdiploidy, hypodiploidy, trisomy 4 and 10 and intrachromosomal amplification of 57 chromosome 21) or chromosomal translocation (MLL-AF4, ETV6-RUNX1, E2A-PBX1 58 and BCR-ABL1) [3]. Fortunately, irrespective of the genesis of the disease, there has 59 been continuous improvement in prognosis in both children and adults, with most 60 achieving complete remission following treatment using the present standard-of-care [4].61 However, disease relapse does occur in specific patients, and often the emerging disease 62 will mani...

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Section: Methodsmentioning

confidence: 99%

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

Nair

Piktel

Thomas

et al. 2019

Preprint

Self Cite

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“…Leukemic cells with high expression of p27 are more resistant to Cytarabine and Vincristine chemotherapies. On the other hand, the ectopic expression of miR-221 during the co-culturing of ALL cells with the human bone marrow cells significantly sensitized the cells to these cytotoxic drugs [98].…”

Section: Involvement Of Tme-associated Mirnas In Cancer Therapy Resismentioning

confidence: 99%

The Interplay between MicroRNAs and the Components of the Tumor Microenvironment in B-Cell Malignancies

El‐Daly

Bayraktar

Anfossi

et al. 2020

IJMS

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An increased focus is being placed on the tumorigenesis and contexture of tumor microenvironment in hematopoietic and solid tumors. Despite recent clinical revolutions in adoptive T-cell transfer approaches and immune checkpoint blockade, tumor microenvironment is a major obstacle to tumor regression in B-cell malignancies. A transcriptional alteration of coding and non-coding RNAs, such as microRNAs (miRNAs), has been widely demonstrated in the tumor microenvironment of B-cell malignancies. MiRNAs have been associated with different clinical-biological forms of B-cell malignancies and involved in the regulation of B lymphocyte development, maturation, and function, including B-cell activation and malignant transformation. Additionally, tumor-secreted extracellular vesicles regulate recipient cell functions in the tumor microenvironment to facilitate metastasis and progression by delivering miRNA contents to neighboring cells. Herein, we focus on the interplay between miRNAs and tumor microenvironment components in the different B-cell malignancies and its impact on diagnosis, proliferation, and involvement in treatment resistance.

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“…Bone marrow microenvironment is important also in acute lymphoblastic leukemia (ALL) [140]. ALL cells exposed to primary human bone marrow niche cells, including bone marrow stromal cells (BMSC) and primary human osteoblasts, show a decrease in miR-221 and -222 levels, with an increase of the target protein p27 (CDKN1B), leading to the accumulation of tumor cells in the G 0 phase and resistance to chemotherapy-induced death [141]. Moreover, in Chronic Myelogenous Leukemia (CML), ECs in the bone marrow niche express high level of miR-126 and supply it to CML cells, likely through EV-mediated miRNA trafficking, causing decreased cell cycling and apoptosis, and increased frequency of dormant leukemia cells [142].…”

Section: Dormancy In the Metastatic Niche Is Induced By Mirnas In Canmentioning

confidence: 99%

Cancer-Derived Extracellular Vesicle-Associated MicroRNAs in Intercellular Communication: One Cell’s Trash Is Another Cell’s Treasure

Mills

Capece

Cocucci

et al. 2019

IJMS

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Several non-protein-coding genomic regions, previously marked as “junk DNA”, have been reported to be transcriptionally active, giving rise to non-coding RNA species implicated in fundamental biological and pathological processes. In particular, microRNAs (miRNAs), a class of small non-coding RNAs mediating post-transcriptional gene silencing, are causally involved in several human diseases, including various cancer types. Extracellular vesicles (EVs) are membranous structures physiologically released by most cell types. Initially, they were considered a “waste-removal” mechanism, through which cells could dispose unnecessary material and organelles. It is now widely demonstrated that EVs also play a critical role in intercellular communication, mediating the horizontal transfer of lipids, proteins, and genetic material. A paradigm shift in the biology of miRNAs was represented by the discovery that EVs, especially from cancer cells, contain miRs. EV-associated miRs act as autocrine, paracrine and endocrine factors, participating in cancer pathogenesis by modulating intercellular communication. Noteworthy, these formerly neglected molecules are now considered the next generation of cancer “theranostic” tools, with strong clinical relevance. In this review, we aim to summarize the most recent findings regarding EV-associated miRs in cancer pathogenesis and in the development of novel anti-neoplastic diagnostic and therapeutic approaches.

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

Cited by 32 publications

References 50 publications

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

Targeting the dysfunctional mitochondrial respiration in drug resistant B-cell acute lymphoblastic leukemia

The Interplay between MicroRNAs and the Components of the Tumor Microenvironment in B-Cell Malignancies

Cancer-Derived Extracellular Vesicle-Associated MicroRNAs in Intercellular Communication: One Cell’s Trash Is Another Cell’s Treasure

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