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Haematological Cancer
Proteomics in Myeloproliferative Disorders
a report by
Pascal Mossuz
Haematology Laboratory, University Hospital Grenoble
Myeloproliferative disorders (MPDs) are haematopoietic stem cell (nano-LC MS/MS) has been applied to characterise the proteome of
malignancies characterised by overproduction of one or more mature several organisms, organelles and multiprotein complexes.
10–12
myeloid lineage. The term ‘myeloproliferative syndrome’ was first Progress in genome sequencing and better, faster bio-informatics
introduced in 1951 by Dameshek,
1
who defined chronic myeloid tools have increased the potential of proteomics as a powerful
leukaemia (CML), polycythaemia vera (PV), essential thrombo- analytical tool. Comparison of protein profiles, obtained from
cythaemia (ET) and idiopathic myelofibrosis (IMF) as a group of closely biological fluids or tissue sections, reveals an informative diagnostic
inter-related neoplasms caused by proliferate activity of the bone approach for tumour discrimination and for the discovery of the
marrow cells. diagnostic markers of solid tumours.
13
In the field of haematology,
proteomics has allowed the investigation of proteome modifications
Chronic myeloid leukaemia was the first neoplasia to be associated with associated with different haematological neoplasms,
14–16
identified
a specific chromosomal abnormality, and became the paradigm for therapy-related proteomes
17
and predicted clinical behaviour in adult
targeted therapy.
2
The central role of the tyrosine-kinase activity and lymphocytic leukaemia (ALL).
18
Evidence that some solid tumors and
fusion of the oncoprotein BCR-ABL in reciprocal translocation between AML are associated with quantitative changes of serum proteins has
chromosomes 9 and 22 – t(9;22)(q34;q11) – made it a suitable drug been published.
19–21
target. It is now the front-line CML therapy.
3
The molecular mechanisms
of PV, ET and IMF remained elusive. The clonal nature of these disorders This review illustrates the ability of proteomic approaches to gain
was objectified by their capacity to form endogenous colonies without insight into MPD physiopathology in three ways:
haematopoietic factor. In 2005, 50 years after Dameshek’s definition,
several groups identified the molecular basis of these MPDs as a JAK2- • research for biomarkers;
V617F ‘gain-of-function’ mutation.
4–7
The role of the JAK2-V617F • investigation of molecular mechanisms of drug resistance; and
mutation has been widely documented, along with its critical role in the • phenotypic characterisation of patients.
pathogenesis of MPD-Phi.
8
Proteomics Insights into Myeloproliferative Disorders
The term ‘proteome’ was proposed by Wilkins et al. in 1995 and referred
to the whole set of proteins present in a cell or a biological fluid at a given Serum Biomarker Identification
time. The proteome is a fundamentally dynamic entity that reflects the The fact that the allelic ratio (JAK2-V617/JAK2-wild-type) can differ
best functional status of a biological system. There is increasing evidence between patients, in the same patient between cells and during
that the large range of gene products is not necessarily driven by an disease follow-up suggests that the JAK2-V617F burden may have a
alteration of levels of transcript. clinical impact.
22
It was initially suggested that the haematological and
Due to messenger RNA (mRNA) alternative splicing, allelic variations
Pascal Mossuz works in the Haematology Laboratory at
and post-translational modifications, a genome can produce over a
University Hospital Grenoble, where he is responsible for the
million protein species. The proteome represents a dramatic expansion
unit dedicated to the investigation of haematopoiesis
and alteration of the genome message, and as such is a very promising
problems, including the diagnosis of myeloproliferative
disorders through clonogenic cultures. His main focus has
field of investigation as a complement to mRNA-based measurement
been working towards the standardisation of diagnostic
and may achieve significant insights into complex biological systems.
9 criteria for polycythaemia vera (PV) and essential
thrombocythaemia (ET), and he has published numerous
Proteomics refers to the comprehensive study of the proteome,
papers on the standardisation of an endogenous colony
including detection, identification, dosage and characterisation of formation assay for the diagnosis of ET and PV and on the diagnostic value of the serum
protein modifications. Proteomic methods have been available in
erythropoietin assay (EPO). Since 2004, he has been responsible for the programme on
proteomics approaches for clinical stratification of haemopathy in the Integrated and
clinical laboratories for several decades, but have been limited to the
Fundamental Nanoscience team at INSERM research centre 836. Dr Mossuz published a first
evaluation of only a few proteins at a time.
study on serum protein profiles in PV, which showed a relation between JAK2 mutational
status and serum protein profile. Using the same strategy, he investigated the relationships
between PV and mutated ET, showing that the impact of the JAK2 mutation on ET phenotype
In the past few years, mass spectrometry (MS) has emerged as an should not correlate to its role in PV. He is developing mass spectrometry (MS)-based
efficient alternative to 2D electrophoresis. This has considerably
quantitative proteomics strategies using both isotope and label-free methods to research the
use of prognostic markers in high-vascular-risk myeloproliferative disorders.
increased the relevance and accuracy of proteomics.
10
Numerous
technical advances have led to MS-based methods as powerful tools
E:
pmassuz@chu-grenable.fr
for the identification of proteins in complex mixtures. Tandem-MS
© TOUCH BRIEFINGS 2008 77
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