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Eosinophilic disorders: Molecular pathogenesis, new classification, and modern therapy

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Before the 1990s, lack of evidence for a reactive cause of hypereosinophilia or chronic eosinophilic leukemia (e.g. presence of a clonal cytogenetic abnormality or increased blood or bone marrow blasts) resulted in diagnosticians characterizing such nebulous cases as ‘idiopathic hypereosinophilic syndrome (HES)’. However, over the last decade, significant advances in our understanding of the molecular pathophysiology of eosinophilic disorders have shifted an increasing proportion of cases from this idiopathic HES ‘pool’ to genetically defined eosinophilic diseases with recurrent molecular abnormalities. The majority of these genetic lesions result in constitutively activated fusion tyrosine kinases, the phenotypic consequence of which is an eosinophilia-associated myeloid disorder. Most notable among these is the recent discovery of the cryptic FIP1L1PDGFRA gene fusion in karyotypically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES, redefining these diseases as clonal eosinophilias. Rearrangements involving PDGFRA and PDGFRB in eosinophilic chronic myeloproliferative disorders, and of fibroblast growth factor receptor 1 (FGFR1) in the 8p11 stem cell myeloproliferative syndrome constitute additional examples of specific genetic alterations linked to clonal eosinophilia. The identification of populations of aberrant T-lymphocytes secreting eosinophilopoietic cytokines such as interleukin-5 establish a pathophysiologic basis for cases of lymphocyte-mediated hypereosinophilia. This recent revival in understanding the biologic basis of eosinophilic disorders has permitted more genetic specificity in the classification of these diseases, and has translated into successful therapeutic approaches with targeted agents such as imatinib mesylate and recombinant anti-IL-5 antibody.

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Clonality studies in hypereosinophilia

One method for establishing a diagnosis of CEL is demonstration of the clonal origin of eosinophils; however, this is frequently not assessed or difficult to confirm in patients lacking cytogenetic abnormalities. Methods for demonstrating clonality include fluorescent in situ hybridization,5 cytogenetic analysis of purified eosinophils,6 and X-chromosome inactivation analysis in females.7, 8 X-inactivation-based assessment of clonality is of limited value in HES because of the predominance of

Reactive and clonal eosinophilia associated with hematologic malignancies

Reactive eosinophilia can be observed with several hematologic malignancies. Eosinophilia is thought to result from the production of cytokines (e.g. IL-3, IL-5, and GM-CSF) from malignant cells in T-cell lymphomas,13 Hodgkin's disease,14 and acute lymphoblastic leukemias.15, 16 Eosinophilia might herald the initial diagnosis or relapse of these conditions.

The list of chromosomal abnormalities in literature-described cases of HES or CEL has grown considerably over the last 30 years. Bain

Biology of the platelet-derived growth factor receptors (PDGFRs)

PDGFRα and PDGFRβ are members of the family of class III receptor tyrosine kinases which also include c-KIT, FLT3, KDR, and c-FMS (reviewed in Ref. [46]). These molecules are characterized by an extracellular ligand-binding domain comprising five immunoglobulin-like structures: a transmembrane (TM) domain, a juxtamembrane (JM) domain, two intracellular tyrosine kinase (TK) domains interrupted by a kinase insert (KI), and a C-terminal domain.47 PDGFRβ is a 190-kDa transmembrane protein expressed

A diagnostic, classification, and treatment algorithm for hypereosinophilia

We have developed a diagnostic algorithm for hypereosinophilia in which detection of the FIP1L1PDGFRA fusion is a nodal point that generates a potentially useful classification and treatment scheme for eosinophilic disorders (Figure 3(A)). In patients whose work-up is negative for secondary causes of eosinophilia, screening for the FIP1L1PDGFRA gene fusion could subsequently be undertaken using either RT-PCR or interphase/metaphase FISH. Because testing for FIP1L1PDGFRA is not widely

Summary

The study of hypereosinophilia was originally rooted in descriptive and morphologic investigations. However, more sophisticated understanding of the molecular network of fusion tyrosine kinase genes in eosinophilic disorders (see Figure 1) now permits a more pathobiologically oriented classification scheme that translates into opportunities for novel therapeutic approaches with imatinib mesylate and other tyrosine kinase inhibitors, and anti-IL-5 antibody therapy.

Investigations have shown the

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