scholarly journals RNAi screening of the tyrosine kinome in primary patient samples of acute myeloid leukemia

2018 ◽  
Author(s):  
David K. Edwards ◽  
Fatma Eryildiz ◽  
Jeffrey W. Tyner
Keyword(s):  
Myeloid Leukemia ◽  
Target Identification ◽  
Treatment Strategies ◽  
Functional Screening ◽  
Multiple Cancer ◽  
Screening Assay ◽  
Protein Target ◽  
Cancer Types ◽  
Tyrosine Kinome ◽  
Acute Myeloid

AbstractTargeted therapy has proven to be successful in improving outcomes across multiple cancer types. However, many challenges still remain for implementation of this strategy in most patient cohorts, especially with the challenges of identifying the specific mutations or abnormalities in a heterogeneous tumor that are functionally significant. Previously, we developed a functional screening assay, RNAi-assisted protein target identification (RAPID) technology, which evaluates the viability of tumor cells after exposure to siRNAs against members of the tyrosine kinome and NRAS/KRAS. Here, we publish the comprehensive results of this screen for 332 primary AML patient samples. Data from these screening efforts have already helped identify previously unknown therapeutic targets, and will continue to provide insights into better treatment strategies for these patients.

scholarly journals Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications

2021 ◽  
Vol 5 (16) ◽  
pp. 3102-3112
Author(s):  
Marta Lopes ◽  
Tiago L. Duarte ◽  
Maria J. Teles ◽  
Laura Mosteo ◽  
Sérgio Chacim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Transferrin Saturation ◽  
Treatment Strategies ◽  
Leukemic Cells ◽  
Cancer Types ◽  
Iron Profile ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer, but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in patients with AML at diagnosis and explored the mechanisms involved using the syngeneic MLL-AF9–induced AML mouse model. We found that AML is a disorder with a unique iron profile, not associated with inflammation or transfusion, characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that the AML-induced loss of erythroblasts is responsible for iron redistribution and increased TSAT. We also show that AML progression is delayed in mouse models of systemic iron overload and that elevated TSAT at diagnosis is independently associated with increased overall survival in AML. We suggest that TSAT may be a relevant prognostic marker in AML.

scholarly journals Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications

2020 ◽  
Author(s):  
Marta Lopes ◽  
Tiago L. Duarte ◽  
Maria J. Teles ◽  
Laura Mosteo ◽  
Sérgio Chacim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mouse Model ◽  
Myeloid Leukemia ◽  
Transferrin Saturation ◽  
Treatment Strategies ◽  
Leukemic Cells ◽  
Cancer Types ◽  
Iron Profile ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis and limited treatment strategies. Determining the role of cell-extrinsic regulators of leukemic cells is vital to gain clinical insights into the biology of AML. Iron is a key extrinsic regulator of cancer but its systemic regulation remains poorly explored in AML. To address this question, we studied iron metabolism in AML patients at diagnosis and mechanisms involved using the syngeneic MLL-AF9-induced AML mouse model. We found that AML is a disorder with a unique iron profile not associated with inflammation or transfusion and characterized by high ferritin, low transferrin, high transferrin saturation (TSAT), and high hepcidin. The increased TSAT in particular, contrasts with observations in other cancer types and in anemia of inflammation. Using the MLL-AF9 mouse model of AML, we demonstrated that leukemic blasts take up iron and that the AML-induced loss of erythroblasts is responsible for iron redistribution and an increase in TSAT. We also show that elevated TSAT at diagnosis is independently associated with increased overall survival in AML and suggest that TSAT may be a relevant prognostic marker in AML.

Treatment Strategies for Therapy-related Acute Myeloid Leukemia

2020 ◽  
Vol 20 (3) ◽  
pp. 147-155 ◽  
Author(s):  
Prajwal Dhakal ◽  
Bimatshu Pyakuryal ◽  
Prasun Pudasainee ◽  
Venkat Rajasurya ◽  
Krishna Gundabolu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Strategies ◽  
Acute Myeloid

scholarly journals Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 82-101 ◽  
Author(s):  
Bob Löwenberg ◽  
James D. Griffin ◽  
Martin S. Tallman
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
Promyelocytic Leukemia ◽  
Remission Induction ◽  
Novel Drugs ◽  
Acute Myeloid

Abstract The therapeutic approach to the patient with acute myeloid leukemia (AML) currently evolves toward new frontiers. This is particularly apparent from the entree of high-throughput diagnostic technologies and the identification of prognostic and therapeutic targets, the introduction of therapies in genetically defined subgroups of AML, as well as the influx of investigational approaches and novel drugs into the pipeline of clinical trials that target pathogenetic mechanisms of the disease. In Section I, Dr. Bob Löwenberg reviews current issues in the clinical practice of the management of adults with AML, including those of older age. Dr. Löwenberg describes upcoming possibilities for predicting prognosis in defined subsets by molecular markers and reviews experimental strategies to improve remission induction and postinduction treatment. In Section II, Dr. James Griffin reviews the mechanisms that lead to activation of tyrosine kinases by mutations in AML, the consequences of that activation for the cell, and the opportunities for targeted therapy and discusses some examples of developing novel drugs (tyrosine kinase inhibitors) and their effectiveness in AML (FLT3). In Section III, Dr. Martin Tallman describes the evaluation and management of patients with acute promyelocytic leukemia, a notable example of therapeutic progress in a molecularly defined entity of leukemia. Dr. Tallman focuses on the molecular genetics of APL, current curative treatment strategies and approaches for patients with relapsed and refractory disease. In addition, areas of controversy regarding treatment are addressed.

scholarly journals Use of carbapenems and glycopeptides increases risk for Clostridioides difficile infections in acute myeloid leukemia patients undergoing intensive induction chemotherapy

2020 ◽  
Vol 99 (11) ◽  
pp. 2547-2553
Author(s):  
Olivier Ballo ◽  
Eva-Maria Kreisel ◽  
Fagr Eladly ◽  
Uta Brunnberg ◽  
Jan Stratmann ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Bacterial Infections ◽  
Treatment Strategies ◽  
Length Of Hospital Stay ◽  
Infectious Complications ◽  
Clostridioides Difficile ◽  
Acute Myeloid

Abstract Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.

scholarly journals New Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise

2019 ◽  
Vol 20 (8) ◽  
pp. 1983 ◽  
Author(s):  
Stephan R. Bohl ◽  
Lars Bullinger ◽  
Frank G. Rücker
Keyword(s):  
Acute Myeloid Leukemia ◽  
Patient Outcomes ◽  
Myeloid Leukemia ◽  
Treatment Strategies ◽  
Gemtuzumab Ozogamicin ◽  
Molecular Heterogeneity ◽  
Targeted Agents ◽  
Fda Approval ◽  
Cytotoxic Treatment ◽  
Acute Myeloid

The therapeutic approach for acute myeloid leukemia (AML) remains challenging, since over the last four decades a stagnation in standard cytotoxic treatment has been observed. But within recent years, remarkable advances in the understanding of the molecular heterogeneity and complexity of this disease have led to the identification of novel therapeutic targets. In the last two years, seven new targeted agents (midostaurin, gilteritinib, enasidenib, ivosidenib, glasdegib, venetoclax and gemtuzumab ozogamicin) have received US Food and Drug Administration (FDA) approval for the treatment of AML. These drugs did not just prove to have a clinical benefit as single agents but have especially improved AML patient outcomes if they are combined with conventional therapy. In this review, we will focus on currently approved and promising upcoming agents and we will discuss controversial aspects and limitations of targeted treatment strategies.

scholarly journals The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells

2020 ◽  
Vol 38 (6) ◽  
pp. 1664-1676
Author(s):  
Małgorzata Opydo-Chanek ◽  
Iwona Cichoń ◽  
Agnieszka Rak ◽  
Elżbieta Kołaczkowska ◽  
Lidia Mazur
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Strategies ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
Acute Myeloid Leukemia Cells ◽  
Induced Apoptosis ◽  
Acute Myeloid

Summary One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.

scholarly journals RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2238-2245 ◽  
Author(s):  
Jeffrey W. Tyner ◽  
Denise K. Walters ◽  
Stephanie G. Willis ◽  
Mary Luttropp ◽  
Jason Oost ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Cancer Genetics ◽  
Janus Kinase ◽  
Functional Assay ◽  
Functional Screening ◽  
Screening Assay ◽  
Activating Mutations ◽  
Rnai Technology ◽  
Tyrosine Kinome

Despite vast improvements in our understanding of cancer genetics, a large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of numerous types of cancer, but identification and validation of tyrosine kinase targets in cancer can be a time-consuming process. We report the establishment of an efficient, functional screening assay using RNAi technology to directly assess and compare the effect of individually targeting each member of the tyrosine kinase family. We demonstrate that siRNA screening can identify tyrosine kinase targets containing activating mutations in Janus kinase (JAK) 3 (A572V) in CMK cells and c-KIT (V560G) in HMC1.1 cells. In addition, this assay identifies targets that do not contain mutations, such as JAK1 and the focal adhesion kinases (FAK), that are crucial to the survival of the cancer cells. This technique, with additional development, might eventually offer the potential to match specific therapies with individual patients based on a functional assay.

Sign in / Sign up

Export Citation Format

Share Document