Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia.

Sara Ribeiro,Jamshid S Khorashad,Anna M Eiring

doi:10.3390/cancers13205055

Abstract

Simple SummaryAML is a heterogenous malignancy with a variety of underlying genomic abnormalities. Some of the genetic aberrations in AML have led to the development of specific inhibitors which were approved by the Food and Drug Administration (FDA) and are currently used to treat eligible patients. In this review, we describe five gene mutations for which approved inhibitors have been developed, the response of AML patients to these inhibitors, and the known mechanism(s) of resistance. This review also highlights the significance of developing function-based screens for target discovery in the era of personalized medicine.Acute myeloid leukemia (AML) is a highly heterogeneous malignancy characterized by the clonal expansion of myeloid stem and progenitor cells in the bone marrow, peripheral blood, and other tissues. AML results from the acquisition of gene mutations or chromosomal abnormalities that induce proliferation or block differentiation of hematopoietic progenitors. A combination of cytogenetic profiling and gene mutation analyses are essential for the proper diagnosis, classification, prognosis, and treatment of AML. In the present review, we provide a summary of genomic abnormalities in AML that have emerged as both markers of disease and therapeutic targets. We discuss the abnormalities of RARA, FLT3, BCL2, IDH1, and IDH2, their significance as therapeutic targets in AML, and how various mechanisms cause resistance to the currently FDA-approved inhibitors. We also discuss the limitations of current genomic approaches for producing a comprehensive picture of the activated signaling pathways at diagnosis or at relapse in AML patients, and how innovative technologies combining genomic and functional methods will improve the discovery of novel therapeutic targets in AML. The ultimate goal is to optimize a personalized medicine approach for AML patients and possibly those with other types of cancers.

Highlights

The introduction of imatinib as a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 revolutionised the treatment of patients with chronic myeloid leukaemia (CML), paving the path for the development of other targeted inhibitors in various types of cancers [1]
CML was a malignancy associated with early death from progression to acute leukaemia or from side effects associated with bone marrow transplantation, which was the only curative option
The clinical practice of Acute myeloid leukemia (AML) is changing mainly due to fast moving genomic technologies which have provided a more detailed picture of the underlying causes of AML, as well as innovations in the design and production of targeted and specific inhibitors. These advances are shifting the treatment of AML from non-specific chemotherapy toward personalized medicine, where AML patients are treated with specific inhibitors based on the specific genomic abnormalities of their leukaemia cells

Summary

Introduction

In acute myeloid leukaemia (AML), for instance, an average of 13 genetic abnormalities can be observed per patient, and the heterogeneity of the disease along with ambiguity of the main driver among the detected mutations may explain why the development of novel inhibitors for AML has not been as successful [6]. The principle of personalised medicine is to identify the main pathway(s) that are essential for survival of the leukaemia cells and to target them in a patient-specific manner The identification of these pathways can be achieved through genomic techniques such as RNA sequencing or whole exome sequencing. We will briefly discuss how functional genomics might be used for identification of potential therapeutic targets in a personalised medicine approach for the clinical management of AML patients

PML-RARA

Functional Genomics and Target Discovery

Findings

Conclusions