Abstract 3037: Stromal cell activation of MAPK signaling pathways mediates resistance to MERTK inhibition in acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) remains a life threatening malignancy in children. Considerable progress has been made in elucidating the new diagnostic and prognostic markers over the past decades. The precise etiology remains unclear. Therefore, it is essential to evaluate the activation of the components of cellular signaling pathways to understand AML signaling and to design the most successful approach for combinational therapies and new kinase inhibitors. In this study, we used a high-throughput PepChipTMKinomics microarray system containing 976 different kinase substrates and assayed primary leukemic samples of 96 AML patients to produce an exceptionally detailed map of kinome enzymatic activities towards predefined peptide substrates. The generated profiles provide a comprehensive insight in signaling pathways active in AML patients. As expected the activation of proteins belonging to MAPK signaling, PI3K/AKT signaling, cell cycle regulation, apoptosis and insulin signaling pathways along with the signaling receptors and immune system regulators were found. Unsupervised hierarchical cluster analysis separates the AML blast profiles based on 192 peptide activities into two clusters. Cumulative incidence of relapse (CIR) was significantly higher in the patients of cluster-2. Peptide activity patterns were independent of patient characteristics. In addition, with Gaussian network modeling, a total of 540 peptides (55%) showed at least one peptide-peptide association without a prior assumptions whereas 74 peptides (7.5%) had >39 nodes suggesting to be potential interesting signaling hubs. Among these 74 peptides, 10 peptides were identified in cluster-1 and 50 peptides were in cluster-2. Thus, this total analysis defined peptides correlated to low incidence for relapse, for examples AKT1, HGFR, RGS7 and to high incidence for relapse for instance, proteins involve in MAPK pathways (RAF1, RAC1,14-3-3 eta) and cell cycle regulation and cellular growth (c-Myc, FOXO3A, RBL1). In conclusion, our study demonstrates the feasibility of peptide activity profiling to identify two active signaling network clusters in pediatric AML correlated to CIR. Highly correlated peptides belonging to cluster-2 provide stronger leads for selection of novel targets in future therapeutics. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Deregulation of Signaling Pathways in Acute Myeloid Leukemia

Seminars in Oncology ◽

10.1053/j.seminoncol.2008.04.004 ◽

2008 ◽

Vol 35 (4) ◽

pp. 336-345 ◽

Cited By ~ 98

Author(s):

Claudia Scholl ◽

D. Gary Gilliland ◽

Stefan Fröhling

Keyword(s):

Acute Myeloid Leukemia ◽

Signaling Pathways ◽

Myeloid Leukemia ◽

Acute Myeloid

Download Full-text

Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment

Blood ◽

10.1182/blood-2018-04-845420 ◽

2019 ◽

Vol 133 (5) ◽

pp. 446-456 ◽

Cited By ~ 17

Author(s):

Amina M. Abdul-Aziz ◽

Yu Sun ◽

Charlotte Hellmich ◽

Christopher R. Marlein ◽

Jayna Mistry ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Stromal Cells ◽

Myeloid Leukemia ◽

Stromal Cell ◽

Cell Senescence ◽

Senescent Phenotype ◽

Age Related ◽

Acute Myeloid

Abstract Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a+ senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the “benign” senescent cells that surround and support AML.

Download Full-text

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

Journal of Applied Mathematics ◽

10.1155/2018/2983138 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 1

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.

Download Full-text

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

SSRN Electronic Journal ◽

10.2139/ssrn.3305572 ◽

2018 ◽

Cited By ~ 1

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

Download Full-text

PVRIG is a novel NK cell immune checkpoint receptor in acute myeloid leukemia

Haematologica ◽

10.3324/haematol.2020.258574 ◽

2020 ◽

pp. 0-0

Author(s):

Jessica Li ◽

Sarah Whelan ◽

Maya F. Kotturi ◽

Deborah Meyran ◽

Criselle D’Souza ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Cell Surface ◽

Nk Cells ◽

Immune Checkpoint ◽

Myeloid Leukemia ◽

Cell Activation ◽

Nk Cell ◽

Blocking Antibody ◽

Poliovirus Receptor ◽

Acute Myeloid

This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased. To understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumour cell recognition, cytokines (IL-2 and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum (ER) and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti- PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIGPVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.

Download Full-text

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

Oncology Reviews ◽

10.4081/oncol.2012.e8 ◽

2012 ◽

Vol 6 (1) ◽

pp. 8 ◽

Cited By ~ 65

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.

Download Full-text