Proteomics in Acute Myelogenous Leukaemia (AML): Methodological Strategies and Identification of Protein Targets for Novel Antileukaemic Therapy

Abstract

Enduring efforts into determination of the molecular biological status of acute myelogenous leukaemia (AML), a stem cell disease characterised by distinct blastic differentiation blocks and their extensive growth, continue to provide us with prognostically important information for more than half of all patients. In subsets of AML, molecular diagnostics rigorously guide the clinician toward the choice of optimal therapy. The in-depth characterization of leukemogenesis associated genetic alterations, such as the combined presence of activating mutations of tyrosine kinases together with altered transcription factors, and the documented impact of these mutations upon prognosis of AML, suggests AML as a primary candidate for pioneering proof-of-principle studies with new high throughput protein analysis techniques. This review aims to introduce the reader to proteomic methodology, e.g. two-dimensional polyacrylamide gel electrophoresis, mass spectrometry, SELDI and protein arrays. Examples of its use, including single cell phosphoprotein profiling in risk stratification, the probing of cellular effects of conventional chemotherapeutics and novel target determination are presented. Based on original proteomic analysis of AML, molecular characteristics of AML, in addition to knowledge of conventional therapeutics and novel drugs, we attempt to forecast the influence of proteomics in therapy development for AML.

A Distinct p53 Protein Isoform Signature Reflects the Onset of Induction Chemotherapy for Acute Myeloid Leukemia

“…A constant challenge is therefore to offer effective therapy to the older patients where low toxicity therapy is needed to obtain disease control (6 -8). The development of molecular targeted therapy with attenuated toxicity may be the most effective way of obtaining increased overall survival for AML patients (9,10).…”

Proteomics in Clinical Trials and Practice

“…For example, Hu et al (54) found that heat shock protein 70 was up-regulated in ovarian cancer cell lines using SELDI-TOF-MS, and treatment with a heat shock protein 70 inhibitor stunted growth of the cell line (54). Similar studies in vitro and in mouse models have been performed in other malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, colon cancer, hepatocellular carcinoma, and breast cancer (55)(56)(57)(58).…”

High content analysis of histone acetylation in human cells and tissues

“…To date, image based methods used for assessing and quantifying epigenetic changes include electron microscopy (Hendzel et al, 1998;Khorasanizadeh, 2004), image correlation spectroscopy (Fejes Toth et al, 2004;Gorisch et al, 2005), confocal imaging and flow cytometry (Le Beyec et al, 2007), high resolution texture analysis of chromatin phenotype (Mohamed et al, 2007), in situ localisation methods (Tumbar et al, 1999;Verschure et al, 1999), protein chromatin interaction studies (Musri et al, 2006;Padilla-Parra et al, 2008) which in some instances include complex proteomics based analysis (Sjoholt et al, 2005) or can be coupled to nucleosomal arrays (Sous et al, 2004). In light of these methods, which each have their obvious advantages the main benefit of the method proposed in this article, is its simplicity.…”