Systematic Multi-Parametric Analysis of Acute Myeloid Leukemia (AML) Flow Cytometry Drug Screens using Flowty

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease, making it difficult to treat. The standard treatment is intensive chemotherapy and has not changed in 40 years. However, recently new drugs and as less intensive treatment regimens have been approved in the US and in Europe. However. With a larger therapeutic toolbox, there is an urgent need for predictive biomarkers to offer the optimal treatment for the patient, also referred to as precision medicine. This project investigated AML flow cytometry drug screens using the unpublished analytical application, Flowty. Cellular subpopulations present in AML bone marrow samples were visualized based on their phenotypic expression of the biomarkers CD34, CD38, CD33, CD45, CD64, CD117 and HLA-DR, as well as granularity. This enabled investigation of whether AML patients and subpopulations with similar differentiation phenotypes have similar drug response. The aim was to explore the possibility of using differentiation phenotype to dictate on AML precision medicine. The heterogeneity in drug response was evident when comparing patients. However, exploring a small patient cohort, subpopulations with similar phenotypic expression demonstrated a similar drug response across patients. Furthermore, future aspects of research were proposed, focusing on additional analysis of the correlations between phenotypic expression and drug response.

Abstract (Swedish)

Akut myeloisk leukemi (AML) är en heterogen sjukdom, vilket gör den svår att behandla. Standardbehandlingen är intensiv kemoterapi och har inte förändrats på 40 år. På senare tid har nya läkemedel och mindre intensiva behandlingsregimer godkänts i USA och Europa. Fler möjliga behandlingsformer gör att det krävs prediktiva biomarkörer och tillförlitliga utvärderingsmetoder för att hitta den optimala behandlingen hos patienterna, så kallat precisionsmedicin. I detta projekt undersöktes flödescytometriska läkemedelsscreens för AML med hjälp av den opublicerade analytiska applikationen Flowty. Cellulära subpopulationer hos patienter med AML visualiserades baserat på deras fenotypiska uttryck av biomarkörerna CD34, CD38, CD33, CD45, CD64, CD117 och HLA-DR, samt granularitet. Detta gjorde det möjligt att undersöka huruvida AML-patienter och subpopulationer med liknande differentieringsfenotyper har liknande läkemedelsrespons. Syftet var att undersöka möjligheten att använda differentieringsfenotyper för att styra precisionsmedicin för AML. Heterogeniteten i läkemedelsresponsen var uppenbar när man jämförde mellan patienter. Subpopulationer med liknande fenotypiskt uttryck visade dock liknande läkemedelsrespons mellan patienter, vid undersökning av en liten patientgrupp. Vidare forskningsaspekter föreslogs, med fokus på ytterligare analys av sambandet mellan fenotypiskt uttryck och läkemedelsrespons.

Popular Abstract

New way of improving survival in aggressive blood cancer disease?

The aggressive blood cancer, called acute myeloid leukemia (AML), has an
extremely low survival in the majority of patients. Comparing cell samples between
patients could be a new way of improving treatment.

Cancer is a devastating disease that can occur in different places in our body, for example in the lungs, brain, or skin. Cancer can also develop in our blood, which is called leukemia. There are different types of blood cancers, or leukemia, one of which is called acute myeloid leukemia (AML). The standard treatment of AML is to give chemotherapy, which is a drug that kills the cancer. However, the drug is so aggressive that it also kills the healthy cells that we need to survive. The majority of patients suffering from AML are elderly. These patients cannot make new cells fast enough to survive this aggressive treatment. Recently, there has been new milder drugs approved for AML in Europe. The cancer looks different between patients and therefore the treatment option should be personalized, which is referred to as precision medicine. To dictate on the precision medicine for AML patients, new characteristics of the patients need to be found.

By comparing patient characteristics and drug response, possibilities of precision medicine can be examined. The patient characteristics investigated were the different bone marrow cell types. It is in the cells of the bone marrow that AML arises, and the cells can be looked at individually in a flow cytometer, which enables comparison of the cells. How well these cells are killed by 40 different drugs, or drug combinations, were also examined. The patients were then compared based on their cell type composition and drug response. This was compared using an unpublished data analysis tool, called "Flowty”. Similar cell types showed similar drug response across patients, indicating that this approach shows promise. However, to further investigate this, more patient cell samples are needed. The results of this project also include the methodologies and data analysis approaches used to examine this. Further investigation in this field, using "Flowty", could hopefully benefit the future of precision medicine for AML, increasing the survival of patients.

• author: Jensen, Augusta
• supervisor: Krister Wennerberg; David Bryder
• organization: Applied Microbiology
• course: KMBM05 20231
• year: 2023
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• keywords: Acute myeloid leukemia, AML, cellular subpopulations, data analysis, precision medicine, Flowty, applied microbiology
• language: English
• id: 9123466
• date added to LUP: 2023-06-13 11:22:47
• date last changed: 2023-06-13 11:22:47