Cellular pharmacokinetics of daunorubicin: Uptake by leukaemic cells in vivo and fate

1985 ◽  
Vol 29 (1) ◽  
pp. 127-129 ◽  
Author(s):  
V. Trillet ◽  
M. Lakhal ◽  
J. Lang ◽  
E. Perrin-Fayolle ◽  
Q. Timour Chah ◽  
...  
Keyword(s):  
Cellular Pharmacokinetics ◽  
Leukaemic Cells

Interaction of normal haemopoiesis and L5222 leukaemic cells in vivo and in vitro

1977 ◽  
Vol 1 (2-3) ◽  
pp. 145-147 ◽  
Author(s):  
D. Hoelzer ◽  
E.B. Harriss ◽  
E. Kurrle
Keyword(s):  
Leukaemic Cells

scholarly journals Growth in vivo of l5178y-r murine leukaemic cells treated in vitro with cis-dichloro bis-(cyclopentylamine) platinum II

1981 ◽  
Vol 43 (1) ◽  
pp. 116-117 ◽  
Author(s):  
I Szumiel ◽  
E Niepokojczycka ◽  
E Godlewska
Keyword(s):  
Leukaemic Cells

scholarly journals Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes

2021 ◽  
Vol 9 ◽  
Author(s):  
Katerina E. Miari ◽  
Monica L. Guzman ◽  
Helen Wheadon ◽  
Mark T. S. Williams
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Clinical Outcomes ◽  
Patient Outcomes ◽  
Therapy Resistance ◽  
Research Field ◽  
Cell Death Pathways ◽  
Leukaemic Cells ◽  
Acute Myeloid

Acute Myeloid Leukaemia (AML) is a commonly occurring severe haematological malignancy, with most patients exhibiting sub-optimal clinical outcomes. Therapy resistance significantly contributes towards failure of traditional and targeted treatments, disease relapse and mortality in AML patients. The mechanisms driving therapy resistance in AML are not fully understood, and approaches to overcome therapy resistance are important for curative therapies. To date, most studies have focused on therapy resistant mechanisms inherent to leukaemic cells (e.g., TP53 mutations), overlooking to some extent, acquired mechanisms of resistance through extrinsic processes. In the bone marrow microenvironment (BMME), leukaemic cells interact with the surrounding bone resident cells, driving acquired therapy resistance in AML. Growing evidence suggests that macrophages, highly plastic immune cells present in the BMME, play a role in the pathophysiology of AML. Leukaemia-supporting macrophage subsets (CD163+CD206+) are elevated in preclinical in vivo models of AML and AML patients. However, the relationship between macrophages and therapy resistance in AML warrants further investigation. In this review, we correlate the potential links between macrophages, the development of therapy resistance, and patient outcomes in AML. We specifically focus on macrophage reprogramming by AML cells, macrophage-driven activation of anti-cell death pathways in AML cells, and the association between macrophage phenotypes and clinical outcomes in AML, including their potential prognostic value. Lastly, we discuss therapeutic targeting of macrophages, as a strategy to circumvent therapy resistance in AML, and discuss how emerging genomic and proteomic-based approaches can be utilised to address existing challenges in this research field.

scholarly journals Granulopoiesis inhibition in acute inflammation: comparative studies in healthy and leukaemic mice

1992 ◽  
Vol 1 (3) ◽  
pp. 171-175
Author(s):  
Mohamad Hamood ◽  
Francis Corazza ◽  
Pierre Francois Bluche ◽  
Hassan El Teraifi ◽  
Pierre Fondu
Keyword(s):  
Acute Inflammation ◽  
Regulatory Mechanism ◽  
Diffusion Chamber ◽  
Colony Growth ◽  
Cell Content ◽  
Humoral Factors ◽  
Leukaemic Cells

It was demonstrated previously that mice undergoing an inflammatory reaction induced by subcutaneous (SC) implantation of copper rods, produce humoral factors that initially enhance, but subsequently inhibit, diffusion chamber (DC) granulopoiesis. This provided evidence that granulopoiesis is under the control of both humoral stimulators and inhibitors. In order to test the granulopoietic regulatory mechanism in leukaemic mice, we investigated the regulatory role of granulopoietic humoral inhibitors during in vivo granulopoiesis. We noticed that mice suffering from acute myeloid leukaemia (AML) are unable to augment the production of these humoral inhibitory factors when acute inflammation is induced, since no change in DC cell content was observed with or without prior inflammation. Moreover, unlike healthy mice, the serum of leukaemic mice withdrawn during the inhibition phase of acute inflammation did not show any inhibitory activity toward granulocyte—monocyte (GM) colony growth in vitro. Our results also show that increased levels of normal humoral inhibitors do not influence the proliferation and/or differentiation of leukaemic cells implanted in diffusion chamber cultures.

scholarly journals EZN-2208 treatment suppresses chronic lymphocytic leukaemia by interfering with environmental protection and increases response to fludarabine

Open Biology ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 190262
Author(s):  
Roberta Valsecchi ◽  
Nadia Coltella ◽  
Daniela Magliulo ◽  
Lucia Bongiovanni ◽  
Lydia Scarfò ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Lymphocytic Leukaemia ◽  
Environmental Protection ◽  
Lymphocytic Leukaemia ◽  
Therapeutic Approaches ◽  
Leukaemic Cells ◽  
Induced Apoptosis ◽  
Early Phases

The transcription factor HIF-1α is overexpressed in chronic lymphocytic leukaemia (CLL), where it promotes leukaemia progression by favouring the interaction of leukaemic cells with protective tissue microenvironments. Here, we tested the hypothesis that a pharmacological compound previously shown to inhibit HIF-1α may act as a chemosensitizer by interrupting protective microenvironmental interactions and exposing CLL cells to fludarabine-induced cytotoxicity. We found that the camptothecin-11 analogue EZN-2208 sensitizes CLL cells to fludarabine-induced apoptosis in cytoprotective in vitro cultures; in vivo EZN-2208 improves fludarabine responses, especially in early phases of leukaemia expansion, and exerts significant anti-leukaemia activity, thus suggesting that this or similar compounds may be considered as effective CLL therapeutic approaches.

Activation by CD40 Ligand Shifts Bcl-2 Family Protein Expression from Death-by-Default to Survival-by-Default.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2811-2811
Author(s):  
Shaun Willimott ◽  
Maria Baou ◽  
Sarah Huf ◽  
Simon Wagner
Keyword(s):  
Peripheral Blood ◽  
Cd40 Ligand ◽  
Mouse Fibroblast ◽  
Systematic Analysis ◽  
L Cells ◽  
Cd38 Expression ◽  
Family Protein ◽  
Leukaemic Cells ◽  
Cd23 Expression

Abstract CLL cells survive and accumulate in vivo and yet leukaemic cells isolated from the peripheral blood rapidly die. We have used mouse fibroblast L-cells transfected with CD40 ligand (CD40L) in combination with IL-4 to reproduce some features of the in vivo microenvironment, which is essential for CLL cell proliferation. As anticipated we found that leukaemic cells survive and proliferate in this system. Also CD23 expression increases, but unexpectedly CD38 expression increased to varying degrees in all patients and CD5 expression decreased. Changes in CD23 and CD38 have been reported in CLL cells in lymph nodes and support the concept that we are able to some extent reproduce the in vivo microenvironment. Next we carried out a systematic analysis of Bcl-2 family proteins by Western Blot analysis. On tissue culture plastic and non-transfected L-cells Bcl-2 is the predominant pro-survival protein. The activator BH3-only protein Bim is expressed together with the sensitiser BH3-only Puma. Both pro-apoptotic Bak and Bax are expressed. By contrast on CD40L-L cell with IL-4 culture Bcl-2 expression decreases and the predominant prosurvival protein is Bcl-xL with a contribution from Mcl-1. The activator BH3-only protein is Bid rather than Bim and the sensitiser BH3 only proteins Puma, Noxa and Bad are expressed. Levels of Bak are significantly decreased but Bax expression is unchanged. Overall it appears that there is an excess of pro-survival Bcl-xL on CD40L-L cells/IL-4 with decreased amounts of Pro-apoptotic Bak. These findings are important when considering the place of treatments directed at pro-survival Bcl-2 family proteins. Large amounts of Bcl-xL is a reservoir to soak up the reduced amount of Bak suggesting that whilst Bcl-2 antagonists will tip the balance towards apoptosis in CLL cells activated by CD40L/IL-4 they are unlikely to be sufficient to cause cell death. However, leukaemic cells in the peripheral blood are dependent on Bcl-2 and have increased amounts of Bak. In this situation reduction in Bcl-2 will release sufficient Bak to cause apoptosis.

Assessment of the sensitivity of leukaemic cells to cytotoxic drugs by bioluminescence measurement of ATP in cultured cells

1986 ◽  
Vol 71 (1) ◽  
pp. 81-88 ◽  
Author(s):  
Rudolf Kuzmits ◽  
Paul Aiginger ◽  
Matthias M. Müller ◽  
Günter Steurer ◽  
Werner Linkesch
Keyword(s):  
Cultured Cells ◽  
Dose Effect ◽  
Blue Dye ◽  
Response Patterns ◽  
Cytostatic Agents ◽  
Drug Induced ◽  
Atp Assay ◽  
Leukaemic Cells

1. A short-term test in vitro is described, which can be used to detect resistance to cytostatic agents in leukaemic cells. Leukaemic cell suspensions were incubated with cytostatic agents and the resulting intracellular ATP concentrations were measured by a bioluminescence ATP assay. 2. There was a clear dose-effect relationship in acute leukaemia and chronic lymphocytic leukaemia cells for drugs used in the treatment of leukaemias. A good correlation was found between the ATP content of leukaemic cells and cell viability as determined by the trypan blue dye exclusion test. 3. Preliminary individual clinical correlations suggest a correlation between the chemosensitivity in vitro and the response patterns in vivo in leukaemia patients. This simple, fast and sensitive method may have application for determination of drug-induced cytotoxicity in leukaemic cells in vitro.

Abi-1-bridged tyrosine phosphorylation of VASP by Abelson kinase impairs association of VASP to focal adhesions and regulates leukaemic cell adhesion

2012 ◽  
Vol 441 (3) ◽  
pp. 889-901 ◽  
Author(s):  
Masahiro Maruoka ◽  
Mizuho Sato ◽  
Yunfeng Yuan ◽  
Masayoshi Ichiba ◽  
Ryosuke Fujii ◽  
...  
Keyword(s):  
Focal Adhesions ◽  
K562 Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Abelson Kinase ◽  
Leukaemic Cells ◽  
Phosphoinositide 3 Kinase ◽  
Proline Rich Region

Mena [mammalian Ena (Enabled)]/VASP (vasodilator-stimulated phosphoprotein) proteins are the homologues of Drosophila Ena. In Drosophila, Ena is a substrate of the tyrosine kinase DAbl (Drosophila Abl). However, the link between Abl and the Mena/VASP family is not fully understood in mammals. We previously reported that Abi-1 (Abl interactor 1) promotes phosphorylation of Mena and BCAP (B-cell adaptor for phosphoinositide 3-kinase) by bridging the interaction between c-Abl and the substrate. In the present study we have identified VASP, another member of the Mena/VASP family, as an Abi-1-bridged substrate of Abl. VASP is phosphorylated by Abl when Abi-1 is co-expressed. We also found that VASP interacted with Abi-1 both in vitro and in vivo. VASP was tyrosine-phosphorylated in Bcr-Abl-positive leukaemic cells in an Abi-1-dependent manner. Co-expression of c-Abl and Abi-1 or the phosphomimetic Y39D mutation in VASP resulted in less accumulation of VASP at focal adhesions. VASP Y39D had a reduced affinity to the proline-rich region of zyxin. Interestingly, overexpression of both phosphomimetic and unphosphorylated forms of VASP, but not wild-type VASP, impaired adhesion of K562 cells to fibronectin. These results suggest that the phosphorylation and dephosphorylation cycle of VASP by the Abi-1-bridged mechanism regulates association of VASP with focal adhesions, which may regulate adhesion of Bcr-Abl-transformed leukaemic cells.

How do retroviral oncogenes induce transformation in avian erythroid cells?

1985 ◽  
Vol 226 (1242) ◽  
pp. 121-126 ◽  
Keyword(s):  
Early Stage ◽  
Erythroid Differentiation ◽  
Erythroid Cells ◽  
Self Renewal ◽  
Erythroid Precursor ◽  
Erythroid Precursors ◽  
Leukaemic Cells ◽  
Transforming Proteins

The v-erb B oncogene, as well as other oncogenes of the src -gene family transform immature erythroid cells from chick bone marrow in vivo and in vitro . The erb B-transformed erythroid cells differ from normal late erythroid precursors (CFU-E) in that they have acquired the capacity to undergo self-renewal as well as to differentiate terminally. They also do not require the normal erythroid differentiation hormone, erythro-poietin, for either process. Cooperation of v-erb B with a second oncogene, v-erb A, results in a differentiation arrest of the transformed cells, which now only use the self-renewal pathway. Studies with conditional and non-conditional mutants in both v-erb B and v-erb A will be presented to elucidate further how the transforming proteins encoded by these oncogenes, gp74 erb B and gp75 gag-erb A , affect the differentiation programme of the infected erythroid precursor with the outcome of hormone-independent leukaemic cells arrested at an early stage of erythroid differentiation.

scholarly journals Infant leukaemia – faithful models, cell of origin and the niche

2021 ◽  
Vol 14 (10) ◽  
Author(s):  
Alasdair Duguid ◽  
Domenico Mattiucci ◽  
Katrin Ottersbach
Keyword(s):  
Ex Vivo ◽  
Central Nervous System Involvement ◽  
Biological Entity ◽  
Single Mutation ◽  
Cell Of Origin ◽  
Established Disease ◽  
Leukaemic Cells ◽  
Distinguishing Features

ABSTRACT For patients and their families, the diagnosis of infant leukaemia is devastating. This disease has not seen the improvements in outcomes experienced with other paediatric leukaemias and it is becoming ever more apparent that infant leukaemia is a distinct biological entity. Insights into some of the distinguishing features of infant leukaemia, such as a single mutation – the MLL-gene rearrangement, the biology of disease aggressiveness and lineage plasticity, and the high incidence of central nervous system involvement, are likely to be gained from understanding the interactions between leukaemic cells and their environment or niche. The origins of infant leukaemia lie in the embryonic haematopoietic system, which is characterised by shifting locations and dynamic changes in the microenvironment. Understanding this foetal or embryonic context is integral to understanding infant leukaemia development. Owing to its rarity and prenatal origins, developing accurate modelling systems for further investigation of infant leukaemia is essential. In this Review, we discuss how available in vitro, ex vivo and in vivo infant leukaemia models contribute to our current understanding of the leukaemia niche in embryonic development, established disease and specialised non-haematopoietic niches. The mechanistic insights provided by accurate models will help identify viable novel therapeutic options.

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