Quantitative evaluation of leukemic mitochondria with a computer-controlled image analyzer

Iwama, Yoshihiko; Eguchi, Mitsuoki

doi:10.1007/bf02899046

Cited by 15 publications

(9 citation statements)

References 16 publications

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“…Mitochondrial gigantism has been recorded also as a manifestation of aging (Murakoshi et al, 1985) and of several diseases, including acute lymphocytic leukemia (Iwama and Eguchi, 1986;Eguchi et al, 19871, thyrotoxicosis (Korenyi-Both et al, 1981), radiation carditis (Maeda, 1982), hyperlipoproteinemia (Gariot et al, 1987), and submandibular gland adenoma (Tandler and Erlandson, 1983).…”

Section: Introductionmentioning

confidence: 97%

“…chondrial enlargement has been ascribed to a reaction to drugs such as cymetidine (Schwartz et al, 1986), propylthiouracil (Aguas et al, 19811, cuprizone (Suzuki, 19691, and other electron-donating ammonia derivatives (Wakabayashi et al, 1984). Mitochondrial gigantism has been recorded also as a manifestation of aging (Murakoshi et al, 1985) and of several diseases, including acute lymphocytic leukemia (Iwama and Eguchi, 1986;Eguchi et al, 19871, thyrotoxicosis (Korenyi-Both et al, 1981), radiation carditis (Maeda, 1982), hyperlipoproteinemia (Gariot et al, 1987), and submandibular gland adenoma (Tandler and Erlandson, 1983).…”

Section: Introductionmentioning

confidence: 99%

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Giant mitochondria distinct from enlarged mitochondria in secretory and ciliated cells of gerbil trachea and bronchioles

et al. 1990

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Numerous mitochondria ranging from slightly larger than normal to several micrometers in diameter (giant) were found in about one-half the serous secretory cells in the surface epithelium of the normal gerbil trachea and proximal bronchi. Tracheal serous cells of mice also were found to contain numerous giant mitochondria. Clara cells of gerbil bronchioles contained abundant giant mitochondria in addition to normal tubular mitochondria and the second population of enlarged spherical mitochondria that have been described in Clara cells of several genera. In contrast, mouse Clara cells revealed the normal tubular and the enlarged spherical mitochondria but no giant mitochondria. A survey of a number of cell types in gerbils failed to disclose hypertrophied mitochondria outside tracheobronchial surface epithelium and bronchioles. The mitochondrial enlargement resulted from an increase of matrix but not cristae. The expansion of matrix displaced the relatively sparse cristae into small collections compressed against the outer membrane. The prevalence of giant mitochondria and of granular endoplasmic reticulum is similar among cells, and these two organelles are codistributed within cells. The megamitochondria and granular reticulum occupy a central stratum, whereas normal mitochondria occur in the apical and basal regions. The giant mitochondria are considered related to a normal biologic activity that is characteristic of respiratory tract epithelium of mice and gerbils selectively and is more prominent in secretory cells than in ciliated cells.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Giant mitochondria distinct from enlarged mitochondria in secretory and ciliated cells of gerbil trachea and bronchioles

et al. 1990

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“…This finding has been further validated by studies showing that B-lymphoid transcription factors (PAX5 and IKZF1) that are critical in normal B-cell development are metabolic gatekeepers that negatively regulate energy metabolism and are mutated or deleted in majority of ALL patients [24, 25]. Furthermore, tumors from B cell ALL patients, but not T cell-ALL, have fewer mitochondria than from patients with myeloid lineage leukemia and abnormality/irregularities in the ALL patient’s mitochondria had a direct correlation to poor treatment prognosis [26]. Also, patient ALL CD34+ cells show upregulation of genes that facilitate glycolysis and downregulation of genes related to the tricarboxylic cycle [27].…”

Section: Discussionmentioning

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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“…activity, a condition that may be important for preventing improper activation of these cells. Indeed, at rest, B cells possess decreased mitochondrial numbers compared to T cells and may possess the least amount of mitochondria among the hematopoietic lineage [7,8]. Upon stimulation B cells increase oxidative phosphorylation, glucose uptake, the citric acid cycle (TCA), and nucleotide biosynthesis [7].…”

Section: Of 25mentioning

confidence: 99%

“…This imbalance of the AMP to ATP ratio indicates increased activity in the LKB1/AMPKa pathway in B cells [38,58]. The result of this seemingly chronic activation of LKB1/AMPka is apparent in the reduced number of mitochondria relative to other cells of the hematopoietic lineage [8,75]. These small, fused mitochondria are relatively inert and do not produce significant levels of ATP [7].…”

Section: Defects In Lkb1/ampka May Alter Mitochondrial Dynamics In B mentioning

confidence: 99%

B Cell Metabolism: An Understudied Opportunity to Improve Immune Therapy in Autoimmune Type 1 Diabetes

Wilson

Moore

2020

Immunometabolism

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Although B lymphocytes are a key cell type that drives type 1 diabetes (T1D), therapeutic targeting of these cells has not ameliorated disease, and it has been impossible to eliminate autoantibody production clinically once it begins. This challenge indicates a need for further dissection of the cellular processes responsible for the development and activation of autoreactive B cells in T1D. Review of the literature in T1D and other autoimmune and hematopoietic diseases indicates that cellular metabolism contributes significantly to lymphocyte development and fate. Unfortunately, little is known about the normal metabolism of B cells and even less is known about the metabolism of B cells in T1D other than what can be inferred from other immune processes. Clues derived from the literature suggest B cell metabolism in T1D is altered including potential differences in OXPHOS, glucose metabolism, fatty-acid metabolism, and reactive-oxygen species stress response. Future research should dissect the metabolic processes at play in autoreactive B cells in T1D. Once understood, B cell metabolism will become a promising target to use in conjunction with current clinical therapies in T1D. Additionally, metabolic changes in B cells may serve as a reliable biomarker for predicting the responsiveness of patients to these immune therapies.

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Quantitative evaluation of leukemic mitochondria with a computer-controlled image analyzer

Cited by 15 publications

References 16 publications

Giant mitochondria distinct from enlarged mitochondria in secretory and ciliated cells of gerbil trachea and bronchioles

Giant mitochondria distinct from enlarged mitochondria in secretory and ciliated cells of gerbil trachea and bronchioles

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

B Cell Metabolism: An Understudied Opportunity to Improve Immune Therapy in Autoimmune Type 1 Diabetes

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