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