We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress hp
Sign In
Advertise with Us
LGC Clinical Diagnostics

Download Mobile App




Potential Screening for Tailoring Treatment of AML

By LabMedica International staff writers
Posted on 17 Dec 2018
Print article
Image: The CellTiter-Glo 3D cell viability assay (Photo courtesy of Promega).
Image: The CellTiter-Glo 3D cell viability assay (Photo courtesy of Promega).
Acute Myeloid Leukemia (AML) is a serious disorder of certain blood-forming cells. In this disease, certain early precursor cells in the bone marrow that usually develop into white blood cells do not mature properly. They remain frozen as primitive cells called blasts, unable to further differentiate and mature.

Leukemia stem cells (LSC), the progenitors for the immature cancerous blood cells, propagate AML, and also play a role in the cancer returning after treatment. Cancer scientists are interested in how genes are expressed in this cell population, because this data may hold clues to resistance to standard therapies and answers to why some patients relapse.

A multidisciplinary team of scientists at the University of Washington Health Sciences (Seattle, WA, USA) and their colleagues obtained samples from patients with AML. LSCs were isolated by fluorescence-activated cell sorting (FACS) and the blast population enriched to more than 90% using immunomagnetic beads from blood samples from five patients with AML. A sixth AML patient sample was used for NOD/SCID IL2R γc−/− engraftment, in order to compare characteristics of pre- and post-engraftment subclones.

The CLIA approved custom assay includes 153 drugs and targeted agents, both FDA approved and investigational, with additional drug combinations. High throughput screens (HTS) were conducted with enriched cells adherent to matrix protein in 384 well plates with eight concentrations of each drug spanning four logs. Viability was assessed with CellTiter-Glo. HTS were performed on LSCs, blasts and pre- as well as post-engraftment AML subclones from the xenograft. Dose-response curves were generated to calibrate drug resistance patterns. Mutation analysis by NGS for a panel of 194 recurrently mutated genes in AML including 37 translocations was also conducted for the LSC and blast populations.

The team reported that AML blasts and LSCs exhibited divergent drug susceptibility patterns. Of 11 drugs commonly used in AML, eight were typical chemotherapy drugs. Five of these compounds were effective against blasts, but none were effective against LSCs, suggesting a possible mechanism for post-treatment relapse or primary refractoriness. LSCs were also resistant to mitomycin-C, an agent that induces DNA interstrand crosslinks and DNA breaks, in contrast to blasts that were variably sensitive. Of note, they identified 12 drugs from eight classes defined by mechanism of action that may target LSCs, in some cases preferentially, when compared with blasts.

The authors concluded that the distinct drug susceptibility patterns of patient-specific LSC and blast populations highlight the potential of an individualized approach to treat AML. LSCs are resistant to S-phase agents used in standard-of-care chemotherapy. Genetically distinct minority resistant LSC subclones present at diagnosis may grow rapidly under some conditions, and contribute to drug resistance and relapse. Incorporating the results of functional drug screening focused on LSC subclones may allow more individualized treatment of AML patients and identify patient-specific therapies that lead to improved outcomes. The study was presented at the 60th Annual Meeting of the American Society of Hematology held December 1-4, 2018, in San Diego, CA, USA.

Related Links:
University of Washington Health Sciences

Gold Member
Flocked Fiber Swabs
Puritan® Patented HydraFlock®
Verification Panels for Assay Development & QC
Seroconversion Panels
New
Binocular Laboratory LED Illuminated Microscope
HumaScope Classic LED
New
Biological Indicator Vials
BI-O.K.

Print article

Channels

Molecular Diagnostics

view channel
Image: Researcher Kanta Horie places a sample in a mass spectrometer that measures protein levels in blood plasma and other fluids (Photo courtesy of WashU Medicine)

Highly Accurate Blood Test Diagnoses Alzheimer’s and Measures Dementia Progression

Several blood tests are currently available to assist doctors in diagnosing Alzheimer's disease in individuals experiencing cognitive symptoms. However, these tests do not provide insights into the clinical... Read more

Immunology

view channel
Image: The findings were based on patients from the ADAURA clinical trial of the targeted therapy osimertinib for patients with NSCLC with EGFR-activated mutations (Photo courtesy of YSM Multimedia Team)

Post-Treatment Blood Test Could Inform Future Cancer Therapy Decisions

In the ongoing advancement of personalized medicine, a new study has provided evidence supporting the use of a tool that detects cancer-derived molecules in the blood of lung cancer patients years after... Read more

Microbiology

view channel
Image: Schematic representation illustrating the key findings of the study (Photo courtesy of UNIST)

Breakthrough Diagnostic Technology Identifies Bacterial Infections with Almost 100% Accuracy within Three Hours

Rapid and precise identification of pathogenic microbes in patient samples is essential for the effective treatment of acute infectious diseases, such as sepsis. The fluorescence in situ hybridization... Read more
Copyright © 2000-2025 Globetech Media. All rights reserved.