Modelling acute myeloid leukemia (AML): What’s new? A transition from the classical to the modern

Abstract

Acute myeloid leukemia (AML) is a heterogeneous malignancy affecting myeloid cells in the bone marrow (BM) but can spread giving rise to impaired hematopoiesis. AML incidence increases with age and is associated with poor prognostic outcomes. There has been a disconnect between the success of novel drug compounds observed in preclinical studies of hematological malignancy and less than exceptional therapeutic responses in clinical trials. This review aims to provide a state-of-the-art overview on the different preclinical models of AML available to expand insights into disease pathology and as preclinical screening tools. Deciphering the complex physiological and pathological processes and developing predictive preclinical models are key to understanding disease progression and fundamental in the development and testing of new effective drug treatments. Standard scaffold-free suspension models fail to recapitulate the complex environment where AML occurs. To this end, we review advances in scaffold/matrix-based 3D models and outline the most recent advances in on-chip technology. We also provide an overview of clinically relevant animal models and review the expanding use of patient-derived samples, which offer the prospect to create more “patient specific” screening tools either in the guise of 3D matrix models, microphysiological “organ-on-chip” tools or xenograft models and discuss representative examples. Graphical abstract

Standardized assays to monitor drug sensitivity in hematologic cancers

“…While we present ex vivo screening protocols that use the CellTiter-Glo assay or flow cytometry as a read-out, alternative approaches to ex vivo drug sensitivity screening have been established and previously reported, including three-dimensional cell culture models [ 39 – 43 ] and protocols with image-based read-outs [ 19 , 44 – 46 ]. Continuous development of the screening protocols, including the consideration of microenvironmental effects on drug sensitivity, is expected to expand their applicability, both when it comes to disease indications and to drug classes that can be assessed.…”

High-Dimensional Mass Cytometry Analysis of Embryonic Antigens and Their Signaling Pathways in Myeloid Cells from Bone Marrow Aspirates in AML Patients at Diagnosis

“…AML represents a heterogeneous group of hematological malignancies characterized by the abnormal proliferation of undifferentiated myeloid progenitors [9]. Various studies have reported aberrant expression of key pluripotency transcription factors (OCT4, NANOG, and SOX2) in different types of solid and hematological tumors [4][5][6].…”

Choosing the Right Cell Line for Acute Myeloid Leukemia (AML) Research

“…Considering the complexity of AML, it is impossible to identify a single cell line to establish a universal disease model. Studies conducted in non-human animal models may not provide accurate results because of differences in AML progression across species [ 7 ]. While studies using primary samples from patients may be more similar to clinical outcomes in patients, they can be diverse due to the varied genotypes of each patient.…”

“…On the other hand, studies using established cell lines are more cost-effective and reproducible but do not account for the variability of clinical features in patients. Therefore, combining studies using established cell lines with those using primary samples can provide more accurate results [ 7 ].…”