Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy.
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 FIP1L1-PDGFRA 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.
Gotlib
Jason
J
Stanford Cancer Center, 875 Blake Wilbur Drive, Room 2327B, Stanford, CA 94305-5821, USA. jason.gotlib@stanford.edu
Cross
N C P
NC
Gilliland
D Gary
DG
D002999:Clone Cells; D004802:Eosinophilia / Q000145:classification / Q000235:genetics / Q000628:therapy; D050939:Gene Fusion; D015321:Gene Rearrangement; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000145:classification / Q000235:genetics / Q000628:therapy