scholarly journals A Dynamic Model of PI3K/AKT Pathways in Acute Myeloid Leukemia

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Yudi Ari Adi ◽  
Fajar Adi-Kusumo ◽  
Lina Aryati ◽  
Mardiah S. Hardianti

Acute myeloid leukemia (AML) is a malignant hematopoietic disorder characterized by uncontrolled proliferation of immature myeloid cells. In the AML cases, the phosphoinositide 3-kinases (PI3K)/AKT signaling pathways are frequently activated and strongly contribute to proliferation and survival of these cells. In this paper, a mathematical model of the PI3K/AKT signaling pathways in AML is constructed to study the dynamics of the proteins in these pathways. The model is a 5-dimensional system of the first-order ODE which describes the interaction of the proteins in AML. The interactions between those components are assumed to follow biochemical reactions, which are modelled by Hill’s equation. From the numerical simulations, there are three potential components targets in PI3K/AKT pathways to therapy in the treatment of AML patient.

2020 ◽  
Vol 11 ◽  
Author(s):  
Huan Shi ◽  
Xin-Yu Li ◽  
Yao Chen ◽  
Xing Zhang ◽  
Yong Wu ◽  
...  

Acute myeloid leukemia (AML) is an aggressive haematological malignancy characterized by highly proliferative accumulation of immature and dysfunctional myeloid cells. Quercetin (Qu), one kind of flavonoid, exhibits anti-cancer property in multiple types of solid tumor, but its effect on acute myeloid leukemia is less studied, and the underlying mechanisms still largely unknown. This study aimed to explore the specific target and potential mechanism of quercetin-induced cell death in AML. First, we found that quercetin induces cell death in the form of apoptosis, which was caspase dependent. Second, we found that quercetin-induced apoptosis depends on the decrease of mitochondria membrane potential (MMP) and Bcl-2 proteins. With quantitative chemical proteomics, we observed the downregulation of VEGFR2 and PI3K/Akt signaling in quercetin-treated cells. Consistently, cell studies also identified that VEGFR2 and PI3K/Akt signaling pathways are involved in the action of quercetin on mitochondria and Bcl-2 proteins. The decrease of MMP and cell death could be rescued when PI3K/Akt signaling is activated, suggesting that VEGFR2 and PI3K/Akt exert as upstream regulators for quercetin effect on apoptosis induction in AML cells. In conclusion, our findings from this study provide convincing evidence that quercetin induces cell death via downregulation of VEGF/Akt signaling pathways and mitochondria-mediated apoptosis in AML cells.


2008 ◽  
Vol 35 (4) ◽  
pp. 336-345 ◽  
Author(s):  
Claudia Scholl ◽  
D. Gary Gilliland ◽  
Stefan Fröhling

2012 ◽  
Vol 6 (1) ◽  
pp. 8 ◽  
Author(s):  
Tiziana Grafone ◽  
Michela Palmisano ◽  
Chiara Nicci ◽  
Sergio Storti

Hematopoiesis, the process by which the hematopoietic stem cells and progenitors differentiate into blood cells of various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Despite the many controls that regulate hematopoiesis, mutations in the regulatory genes capable of promoting leukemogenesis may occur. The <em>FLT3</em> gene encodes a tyrosine kinase receptor that plays a key role in controlling survival, proliferation and differentiation of hematopoietic cells. Mutations in this gene are critical in causing a deregulation of the delicate balance between cell proliferation and differentiation. In this review, we provide an update on the structure, synthesis and activation of the FLT3 receptor and the subsequent activation of multiple downstream signaling pathways. We also review activating FLT3 mutations that are frequently identified in acute myeloid leukemia, cause activation of more complex downstream signaling pathways and promote leukemogenesis. Finally, FLT3 has emerged as an important target for molecular therapy. We, therefore, report on some recent therapies directed against it.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7107-7107
Author(s):  
Arati Rao ◽  
John Andy Livingston ◽  
Sandeep S. Dave

7107 Background: Adolescent and young adults (AYAs) with Acute Myeloid Leukemia (AML) have been shown to have better outcomes with induction chemotherapy when compared to older young adults (OYAs). Multiple psychosocial, treatment, and host-related factors unique to AYAs have been identified but the contribution of disease biology to these outcomes has not yet been fully characterized. The purpose of this study was to evaluate disease biology as it relates to age-specific differences in outcomes for AYAs with AML. Methods: Clinically annotated, microarray data from 425 patients with newly diagnosed AML from two publicly available datasets: GSE1159; and GSE12417 were analyzed. Age-specific cohorts (AYAs ≤ 30 years; n = 58 and OYAs >30 but ≤ 60 years; n=276) were prospectively identified. Patients in GSE1159 were treated according to protocols of the Dutch–Belgian Hematology–Oncology Cooperative group and included 111 patients who ultimately underwent stem-cell transplantation. Patients in GSE12417 were treated per the AMLCG-1999 protocol. Gene expression analysis was conducted by applying previously defined and tested signature profiles reflecting deregulation of oncogenic signaling pathways and altered tumor environment. All statistical analysis was performed using S-plus and survival analysis by Cox proportional-hazards regression was used to assess differences in overall survival (OS) between age-specified study cohorts and a one-sided p-value ≤ 0.05 was considered statistically significant. Results: AYA patients had a significantly better OS (median survival 24.1 months vs. 13.0 months in OYAs; p=0.0285), but there was no difference in Event Free Survival (p=0.23). Analysis of oncogenic pathways revealed that AYA patients likely had better OS because of lower TNF (p=0.03) and higher myc (p=0.02) pathway activation. Conclusions: AML arising in AYAs may represent a distinct biologic entity characterized by unique patterns of deregulated signaling pathways that contributes to OS. We hope these findings will enable clinically meaningful adjustments of treatment strategies in the AYA AML patient population.


2015 ◽  
Vol 114 (3) ◽  
pp. 397-402 ◽  
Author(s):  
Kathleen M. Sakamoto ◽  
Steven Grant ◽  
Diana Saleiro ◽  
John D. Crispino ◽  
Nobuko Hijiya ◽  
...  

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2339-2339 ◽  
Author(s):  
Yoshiki Sumitomo ◽  
Junji Koya ◽  
Keisuke Kataoka ◽  
Takako Tsuruta-Kishino ◽  
Ken Morita ◽  
...  

Abstract Intensive chemotherapy for the treatment of leukemias inevitably provides cellular and metabolic stress to leukemic cells, leading to programmed cell death. In addition, anti-apoptotic property of leukemic cells could easily induce autophagy in response to anti-leukemic treatments and upregulation of autophagy is likely to contribute to the survival of leukemic cells by driving therapy resistance. Given that bone marrow (BM) supports leukemic cell proliferation by various types of stimuli from stromal cells or leukemic cells themselves, it is supposed that BM-occupying leukemic cells and circulating peripheral leukemic cells would have distinct difference in autophagic activity. However, comprehensive understanding of autophagic activity in leukemic cells has not been achieved so far. Here in this study, autophagic activities of leukemic cells in BM and peripheral blood (PB) from murine acute myeloid leukemia (AML) model driven by MLL-ENL fusion gene were evaluated. In the PB and BM from MLL-ENL AML mice, both mature (CD11b+c-Kit-) and immature (CD11b+c-Kit+) MLL-ENL+ leukemic cells showed no difference in apoptotic status by Annexin-V/DAPI staining regardless of c-Kit expression. By contrast, from cell cycle analysis, c-Kit- leukemic cells in the BM were found to have higher frequency of S/G2 phase than PB counterparts, indicating the proliferative potential of BM leukemic cells. When molecules of intracellular signaling pathways regarding proliferation and survival were assessed, components of MAPK and PI3K-mTOR signaling pathways such as Erk1/2, Akt, S6K, and S6 were highly phosphorylated in c-Kit- BM AML cells compared to c-Kit- PB AML cells, implying the importance of activated cytokine signaling in the BM of MLL-ENL AML. For the autophagic evaluation of PB and BM AML cells, MLL-ENL fusion gene was introduced into autophagy sensor mice, GFP-LC3 transgenic mice, enabling us to check autophagy by GFP. PB AML cells from these mice showed decreased GFP intensity compared to BM counterparts, which meant more activated degradation of autophagosome in peripheral AML cells. By western blotting analysis, PB AML cells had the enhanced conversion of LC3A-I to LC3A-II, indicating activation of autophagy. Furthermore, activation of stress responsive pathways such as nuclear localization of Foxo3a and enhanced phosphorylation of eIF2a was observed in c-Kit- PB AML cells. Interpretation of microarray data using public database (GSE9476 and GSE34577) comparing PB and BM cells from clinical AML samples revealed that PB AML cells have significantly higher expression of amino acid transporters. From these results, it is strongly suggested that peripheral AML cells have enhanced autophagic activity in vivo. To elucidate the functional role of activated autophagy in PB AML cells, MLL-ENL fusion gene was introduced into conditional Atg5 or Atg7 knockout mice (Atg5flox/flox or Atg7flox/flox), both of which are essential for autophagy. Interestingly, genetic deletion of Atg5 or Atg7 in irradiated recipients transplanted with Atg5flox/flox or Atg7flox/flox AML cells caused significant increase of apoptotic cells in peripheral leukemic cells and significant decrease of peripheral white blood cell (WBC) counts and donor cell engraftment in PB, whereas Atg5Δ/Δ or Atg7Δ/Δ MLL-ENL AML mice had neither prolonged survival nor reduced leukemia-initiating capacity in serial transplants. Similar to MLL-ENL AML model, genetic deletion of Atg7 in advanced phase of chronic myeloid leukemia (CML) induced by BCR-ABL plus NUP98-HOXA9 fusion genes caused decreased WBC counts and increased apoptosis in peripheral leukemic cells, indicating that circulating leukemic cells favor autophagy for their survival. It is of note that Atg7 deletion had no impact on apoptosis in normal CD11b+ myeloid fraction, implying that loss of Atg7 could spare normal myeloid cells. It remains to be seen what soluble factors could support the survival of AML cells in BM by suppressing autophagy, but our preclinical data provides the therapeutic potential of autophagy inhibition in the treatment of excessive peripheral leukocytosis. It is also highly expected that inhibition of autophagy could be more effective for BM AML cells when combined with chemotherapeutic agent to activate autophagy. Disclosures Sumitomo: Kyowa Hakko Kirin Co., Ltd.: Employment. Kurokawa:Kyowa Hakko Kirin Co., Ltd.: Research Funding, Speakers Bureau; SHIONOGI & CO., Ltd.: Consultancy; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Celgene K.K.: Consultancy, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Research Funding, Speakers Bureau; Sanofi K.K.: Consultancy; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding, Speakers Bureau; Astellas Pharma Inc., : Research Funding, Speakers Bureau; Dainippon Sumitomo Pharma Co.,Ltd.: Research Funding, Speakers Bureau; Asahi Kasei Co.: Research Funding, Speakers Bureau; Pfizer Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; MSD K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co.,Ltd.: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Teijin Pharma Limited: Research Funding; Alexion Pharmaceuticals K.K.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Mitsubishi Tanabe Pharma Corporation: Speakers Bureau; GlaxoSmithKline K.K.: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Yakult Pharmaceutical Industry Co., Ltd.: Speakers Bureau; Ono Pharmaceutical Co.,Ltd.: Speakers Bureau; Miraca Holdings Inc.: Speakers Bureau; CSL Behring K.K.: Speakers Bureau.


2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Kathy keqin Li ◽  
Limin Chen ◽  
Juyan Lu ◽  
Liufei Luo ◽  
Cheng Luo

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Bahaa Razem ◽  
Mohamed Raiteb ◽  
Sanaa El Mrini ◽  
Faiçal Slimani

Abstract Background Myeloid sarcoma is a solid tumor that consists of immature myeloid cells occurring at an extramedullary site. It can present before, concurrent with, or after the diagnosis of acute myeloid leukemia or other myeloproliferative diseases, and a proportion of patients never develop bone marrow infiltration. Only a few isolated cases of pediatric orbital myeloid sarcoma have been reported, and they are often associated with a high misdiagnosis rate. Case report We report a rare case of pediatric orbital myeloid sarcoma associated with blunt trauma in a 3-year-old Caucasian male patient, which was clinically and radiologically misdiagnosed for orbital subperiostal hematoma. The patient underwent a surgical intervention to drain the hematoma when an orbital mass was found. The microscopic, immunologic, and genetic features of the tumor and the myelogram were in favor of LAM2, and the patient was started with chemotherapy with a favorable evolution within 18 months follow-up. Conclusion Orbital myeloid sarcoma usually exhibits clinical and radiological features that can be easily misleading, especially if it happens de novo or as the first manifestation of acute myeloid leukemia. Only a few isolated cases have reported and proposed trauma as a trigger event of the onset of this type of tumor proliferation, but further investigations and evidence are needed to support this hypothesis.


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