scholarly journals Subtractive Interaction Proteomics Reveal a Network of Signaling Pathways Activated by an Oncogenic Transcription Factor in Acute Myeloid Leukemia

2018 ◽  
Author(s):  
Nathalie Guillen ◽  
Maria Wieske ◽  
Andreas Otto ◽  
Afsar Ali Mian ◽  
Michal Rokicki ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Interaction Proteomics ◽  
Oncogenic Transcription Factor ◽  
Acute Myeloid

scholarly journals Subtractive Interaction Proteomics Reveal a Network of Signaling Pathways Activated by an Oncogenic Transcription Factor in Acute Myeloid Leukemia

2018 ◽  
Author(s):  
Nathalie Guillen ◽  
Maria Wieske ◽  
Andreas Otto ◽  
Afsar Ali Mian ◽  
Michal Rokicki ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Cellular Responses ◽  
Therapeutic Interventions ◽  
Cancer Signaling ◽  
Proteomics Approach ◽  
Myeloid Leukemias ◽  
Interaction Proteomics ◽  
Oncogenic Transcription Factor ◽  
Acute Myeloid

SummaryAcute myeloid leukemias (AML) are characterized by recurrent genomic alterations, often in transcriptional regulators, which form the basis on which current prognostication and therapeutic intervention is overlaid. In AML transformation can often be attributed to single chromosomal aberrations encoding oncogenes, such as t(15;17)-PML/RARα or t(6;9)-DEK/CAN but it is unclear how these aberrant transcription factors drive leukemic signaling and influence cellular responses to targeted therapies. Here we show that by using a novel “subtractive interaction proteomics” approach, the high risk AML-inducing oncogene t(6;9)-DEK/CAN directly activates signaling pathways that are driven by the ABL1, AKT/mTOR, and SRC family kinases. The interplay of these signaling pathways creates a network with nodes that are credible candidates for combinatorial therapeutic interventions. These results reveal specific interdependencies between nuclear oncogenes and cancer signaling pathways thus providing a foundation for the design of therapeutic strategies to better address the complexity of cancer signaling.Graphical Abstract

Deregulation of Signaling Pathways in Acute Myeloid Leukemia

2008 ◽  
Vol 35 (4) ◽  
pp. 336-345 ◽  
Author(s):  
Claudia Scholl ◽  
D. Gary Gilliland ◽  
Stefan Fröhling
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Acute Myeloid

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
Keyword(s):  
Mathematical Model ◽  
Acute Myeloid Leukemia ◽  
Numerical Simulations ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Akt Signaling ◽  
Dimensional System ◽  
First Order ◽  
Immature Myeloid Cells ◽  
Acute Myeloid

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.

scholarly journals The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein

2000 ◽  
Vol 20 (6) ◽  
pp. 2075-2086 ◽  
Author(s):  
Ari M. Melnick ◽  
Jennifer J. Westendorf ◽  
Adam Polinger ◽  
Graeme W. Carlile ◽  
Sally Arai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Acute Myeloid

ABSTRACT The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1–ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor α in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.

scholarly journals An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment

2012 ◽  
Vol 6 (1) ◽  
pp. 8 ◽  
Author(s):  
Tiziana Grafone ◽  
Michela Palmisano ◽  
Chiara Nicci ◽  
Sergio Storti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Molecular Therapy ◽  
Tyrosine Kinase Receptor ◽  
Hematopoietic Stem ◽  
Downstream Signaling ◽  
Proliferation And Differentiation ◽  
Acute Myeloid

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.

Evaluating oncogenic pathway dysregulation in adolescents and young adults with acute myeloid leukemia.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7107-7107
Author(s):  
Arati Rao ◽  
John Andy Livingston ◽  
Sandeep S. Dave
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Cox Proportional Hazards ◽  
Psychosocial Treatment ◽  
P Value ◽  
Related Factors ◽  
Disease Biology ◽  
Acute Myeloid

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.

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