Stability and oscillations in a CML model

2017 ◽  
Author(s):  
Irina Badralexi ◽  
Andrei Halanay
Keyword(s):  
Cml Model

Beclin-1 Phosphorylation By BCR-ABL Is Crucial for CML Leukemogenesis By Suppression of Autophagy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 16-16 ◽  
Author(s):  
Chuanjiang Yu ◽  
Sivahari Prasad Gorantla ◽  
Tony Mueller ◽  
Lena Lippert ◽  
Zhenyu Yue ◽  
...  
Keyword(s):  
Overall Survival ◽  
Specific Substrate ◽  
Autophagosome Formation ◽  
Tyrosine Residues ◽  
Abl Kinase ◽  
Autophagy Induction ◽  
Cml Model ◽  
Tki Treatment ◽  
The Impact

Abstract The constitutively activated chimeric Tyrosine kinase BCR-ABL is critical for initiation, progression and maintenance of chronic myelogenous leukemia (CML). Imatinib and second generation BCR-ABL tyrosine kinase inhibitors (TKIs) serve now as standard therapies for Ph+-patients. However, disease persistence occurs frequently and insensitivity of CML stem cells to TKI treatment is discussed as one major reason for this. Recent evidence accumulates, that autophagy, a genetically-regulated process of adaptation to metabolic stress, is involved in TKI-induced cell death. It is hypothesized, that TKI-induced autophagy could allow CML stem cells to become metabolically dormant enabling their survival under conditions that may mimic growth factor deprivation and thereby "antagonize" TKI-induced cell death. However, the molecular mechanism of BCR-ABL and TKI induced autophagy as well as its role as tumor suppressor or promoter is poorly understood. In our study, we aim to identify the precise role of autophagy and its´ effector molecules in a murine CML model. To test whether BCR-ABL regulates autophagy, we measured LC3 as a marker for autophagy in BCR-ABL+-K562 cell. Interestingly, inhibition of BCR-ABL activity by nilotinib led to increased LC3-II expression and punctual LC3 accumulation, indicating, that BCR-ABL activity can suppress autophagy. Consistent with this, Ba/F3 cells expressing BCR-ABL WT induce autophagy, whereas Ba/F3 cell expressing BCR-ABL-T315I fail to induce autophagy by nilotinib treatment, pointing to a BCR-ABL specific autophagy induction than an unspecific effect of TKI treatment. Next, we investigated the proteins involved in BCR-ABL mediated autophagosome formation. Recruitment of VPS34 and ATG14 to Beclin1 was increased in case of nilotinib treatment and could thereby positively regulate autophagosome formation, whereas Rubicon, a negative regulator was less recruited to the Beclin1-complex. To further identify the impact of Beclin1 as a key regulator of autophagy in BCR-ABL-driven leukemia, we used a targeted genetic approach in a CML mouse model. Interestingly, mice transplanted with Belin1 knockdown, BCR-ABL expressing bone marrow showed a less aggressive disease with significantly lower WBC-count, leukemic burden and prolonged overall survival of the mice. In contrast, deletion of ATG5, another central regulator of autophagy, was not able to change disease onset or progression in the CML model. To further clarify the function of Beclin1, we performed biochemical binding analyses and were able to show, that Beclin1 binds to BCR-ABL independent of BCR-ABL kinase activity and Beclin1 is phosphorylated by BCR-ABL. Interestingly, Beclin1 is an exclusive target of BCR-ABL and can not be phosphorylated by other aberrantly activated tyrosine kinases like Flt3-ITD, NPM-ALK and PDGFRA-D842V. In vitro kinase assay with active ABL-kinase confirm Beclin1 as a specific substrate of BCR-ABL. GST pulldown experiments mapped the N-terminal region of Beclin1 to interact with BCR-ABL. Cloning of different phospho-deficient mutants identified tyrosine residues Y233 and Y352 of Beclin1 as the crucial sites for specific BCR-ABL phosphorylation. To test the impact of BCR-ABL mediated Beclin1-phosphorylation on autophagy induction, we generated Beclin1 phospho-mimic (Y233E/Y352E) and phospho-deficient (Y233F/Y352F) mutations. Interestingly, nilotinib treatment fails to induce autophagy in cells expressing the Beclin1 phospho-mimic mutations, thereby highlighting the necessity of Beclin1 in BCR-ABL-mediated autophagy. Expression of Beclin1 mutations in Beclin1 knockout MEFs and K562 cells show decreased binding of UVRAG, ATG14 and VPS34 to Beclin1 Y233E/Y352E, suggesting an important role of Beclin1 phosphorylation for complex stabilization and autophagy suppression. Taken together our findings identify Beclin1 as a specific substrate of BCR-ABL. Downregulation of Beclin1 is associated with a prolonged overall survival of BCR-ABL transplanted animals; direct phosphorylation of Beclin1 on Tyrosine residues Y233 and Y352 lead to LC3 inhibition and suppression of autophagy. Our results thereby highlight the importance of Beclin1 in BCR-ABL-mediated leukemogenesis and show, that autophagy induction in CML cells may be rather a specific Beclin1-BCR-ABL interaction effect than a general microenvironmental stress phenomenon. Disclosures No relevant conflicts of interest to declare.

A Three-Dimensional Numerical Modelling of Atmospheric Pool Boiling by the Coupled Map Lattice Method

2005 ◽  
Author(s):  
A. Gupta ◽  
P. S. Ghoshdastidar
Keyword(s):  
Thermal Diffusion ◽  
Heated Surface ◽  
Pool Boiling ◽  
Three Dimensional ◽  
Coupled Map Lattice ◽  
Lattice Method ◽  
Copper Strip ◽  
Basic Objective ◽  
Cml Model ◽  
Bubble Rising

In the present paper, the characteristic atmospheric pool boiling curve is qualitatively reproduced for water on a temperature controlled thin copper strip having comparable length and breadth by the coupled map lattice (CML) method using a three-dimensional boiling field model. The basic objective of the work is to improve the prediction of the critical heat flux (CHF) with respect to the 2D CML model of Ghoshdastidar et al. [10]. The work models saturated pool boiling of water at 1 bar on a large (much larger than the minimum wavelength of 2D Taylor waves) and thin horizontal copper strip. The pool height is 0.7 mm, indicating thin film boiling. In the present model, it is assumed that boiling is governed by (a) nucleation from cavities on a heated surface, (b) thermal diffusion, (c) bubble rising motion and associated convection, (d) phase change and (e) Taylor instability. The changes with respect to 2D model are primarily with respect to 3D modelling of thermal diffusion and 2D distribution of nucleating cavity sizes. The predicted CHF is 1.57 MW/m2 as compared to the actual value of 1.3 MW/m2 and 0.36 MW/m2 predicted by the 2D CML model of Ghoshdastidar et al. [10]. It can be said that for the first time a coupled map lattice method which is essentially qualitative in nature has been able to predict the CHF of saturated pool boiling of water at 1 bar very close to the actual value.

ON SPATIAL LYAPUNOV EXPONENTS AND SPATIAL CHAOS

2003 ◽  
Vol 13 (05) ◽  
pp. 1163-1181 ◽  
Author(s):  
SHU TANG LIU ◽  
GUANRONG CHEN
Keyword(s):  
Lyapunov Exponents ◽  
Periodic Orbits ◽  
Coupled Map Lattice ◽  
Real Constant ◽  
Coupling Constant ◽  
Fixed Integer ◽  
Spatial Chaos ◽  
Spatially Periodic ◽  
Cml Model

In this paper, we investigate the periodic orbits, spatial Lyapunov exponents, and stability of spatially periodic orbits of the general 2D Logistic system [Formula: see text] where a is a real constant and μ is a parameter. The existence of spatial chaos in the sense of Li and Yorke is proved using the Marotto theorem. These results extend the corresponding results in the 1D Logistic system [Formula: see text] where n0is a fixed integer. These results also improve some existing results of the 2D coupled map lattice (CML) model [Formula: see text] where ε > 0 is the coupling constant.

scholarly journals Microrna-142 Deficiency Promotes Chronic Myeloid Leukemia (CML) Transformation from Chronic Phase (CP) to Blast Crisis (BC)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-4
Author(s):  
Bin Amber Zhang ◽  
Dandan Zhao ◽  
Huafeng Wang ◽  
Chen Liang ◽  
Le Xuan Truong Nguyen ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Chronic Myeloid Leukemia ◽  
Cell Growth ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Differentially Expressed ◽  
Prolonged Survival ◽  
Research Support ◽  
Cml Model

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from the BCR-ABL1 fusion gene that encodes a constitutively activated tyrosine kinase (TK). Although TK inhibitors (TKIs) induce disease remission and prolonged survival in CML patients, a subset are resistant and progress from chronic phase (CP) to blast crisis (BC) with poor prognosis. Understanding the molecular mechanisms of transformation from CP to BC is necessary in the development of effective treatments. Here, we used the inducible SCLtTA/BCR-ABL transgenic CP CML model to study the molecular mechanism of disease evolution. Upon tetracycline withdrawal to induce BCR-ABL expression, both the SCLtTA/BCR-ABL homozygous (homo, i.e., SCLtTA+/+BCR-ABL+/+, hereafter called BCR-ABL) and heterozygous (het, i.e., SCLtTA+/-BCR-ABL+/-) mice developed and died of CP CML without developing BC CML, implying that BCR-ABL dosage is insufficient to induce transformation. MicroRNA (miR)-142 is highly expressed in hematopoietic cells with a critical role in normal hematopoiesis. In miR-142 knockout (KO)(miR-142−/−) mice, hematopoietic stem and progenitor cells expanded with a decrease of hematopoietic output. Loss of miR-142 function has been reported in lymphoma, acute lymphocytic leukemia and acute myeloid leukemia. Of note, we also observed lower levels of miR-142 in CD34+CD38- cells from patients with BC CML versus (vs) patients with CP CML. Thus, we hypothesized that miR-142 insufficiency may promote CML transformation from CP to BC. To test our hypothesis, we generated miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mice and observed increasing leukemic blasts over time after BCR-ABL induction in the blood and bone marrow (BM), but not in miR-142 wt (miR-142+/+)BCR-ABL controls even when the latter became moribund. MiR-142−/−BCR-ABL mice had larger spleens and significantly shorter survival [median: 26 vs 54 days (d); p<0.0001] than miR-142+/+BCR-ABL controls. Of note, while both homo (miR-142−/−) and het (miR-142+/−) miR-142 KO BCR-ABL mice eventually developed BC CML, the former had a significantly faster progression to BC and shorter survival (median: 26 vs 45 d; p=0.003) than the latter, suggesting miR-142 deficiency alone is sufficient to initiate BC transformation in the CP CML model in a dose-dependent manner. Importantly, all these features were recapitulated in congenic recipient mice transplanted with BM Lin-Sca-1+c-Kit+ cells (LSKs, 2000/mouse) from diseased miR-142−/−BCR-ABL mice, suggesting LSKs were enriched in leukemic stem cells and able to reproduce BC. Of note, in an RNA-seq analysis comparing LSKs from diseased miR-142−/−BCR-ABL (BC) and miR-142+/+ BCR-ABL(CP) mice, 504 genes were found differentially expressed. Gene set enrichment analysis (GSEA) showed only four pathways differentially expressed (upregulated); three [i.e., oxidative phosphorylation, glycolysis and adipogenesis] regulating cell metabolism and the fourth regulating protein secretion. Next, we developed a novel CpG-miR-142 mimic oligonucleotide, hereafter called CpG-M-miR-142, to restore miR-142 levels. Treatment with CpG-M-miR-142 (20mg/kg/day, iv, 4 weeks) on day 2 after BCR-ABL induction significantly prolonged survival of miR-142−/−BCR-ABL mice compared with CpG-scramble (SCR) (75% vs 33% survival rate at day 40 after BCR-ABL induction; median survival: not reached vs 25 d; p=0.03). Since we observed lower miR-142 levels in TKI-resistant vs TKI-sensitive CML patients (p=0.02), we selected LSKs from diseased miR-142−/−BCR-ABL and miR-142+/+BCR-ABL mice and exposed them to TKI nilotinib (NIL; 2µM) or vehicle for 72 hours to evaluate if downregulation of miR-142 was associated with TKI resistance. We observed lower apoptosis and higher cell growth in NIL-treated miR-142−/−BCR-ABL LSKs vs NIL-treated miR-142+/+BCR-ABL LSKs. The decreased sensitivity of miR-142−/−BCR-ABL LSKs to TKI was rescued by treatment with CpG-M-miR-142. CpG-M-miR-142 (2µM) plus NIL significantly increased apoptosis and reduced cell growth in miR-142−/−BCR-ABL LSKs compared with SCR+ NIL. We showed a key role of miR-142 deficiency in the transformation of CP CML to BC CML associated with deregulation of metabolic pathways. Restoring miR-142 expression in vivo with CpG-M-miR-142 significantly decreased the BC transformation rate, prolonged survival of miR-142−/−BCR-ABL mice and may increase sensitivity to TKIs. Disclosures Marcucci: Iaso Bio: Membership on an entity's Board of Directors or advisory committees; Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Merck: Other: Research Support (Investigation Initiated Clinical Trial).

A Spatial Frequency Domain Analysis of the Belousov–Zhabotinsky Reaction

2014 ◽  
Vol 24 (03) ◽  
pp. 1450031 ◽  
Author(s):  
Lingzhong Guo ◽  
Yuzhu Guo ◽  
Yifan Zhao ◽  
Stephen A. Billings ◽  
Daniel Coca ◽  
...  
Keyword(s):  
Spatial Frequency ◽  
Frequency Domain ◽  
Dynamical Behavior ◽  
Domain Analysis ◽  
Frequency Domain Analysis ◽  
Bz Reaction ◽  
Temporal Domain ◽  
Temporal System ◽  
Cml Model ◽  
Spatio Temporal

A nonlinear spatio-temporal system identification and analysis approach is used to study the dynamical behavior of the Belousov–Zhabotinsky (BZ) chemical reaction process. In our previous study [Guo et al., 2010],, the dynamical behavior of the BZ reaction in the spatial-temporal domain has been analyzed by identifying a coupled map lattice (CML) model of the process directly from experimental data from a real BZ reaction experiment. In this paper, the frequency domain analysis of the dynamics near equilibrium is carried out by mapping the obtained CML model into higher order spatial frequency response functions to reveal the nonlinear coupling and modulation between the various initial spectral components in the process. As far as we are aware, this is the first study of any real spatio-temporal system using a spatio-temporal domain identification and frequency domain analysis approach.

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