The FIP1L1-PDGFRα fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management

Abstract

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-␣ gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management. IntroductionProtean biologic and clinical presentations characterize idiopathic hypereosinophilia (HES). HES is similar to other diseases given the moniker "diagnosis of exclusion," in that limited understanding of the pathogenesis of the disease has hampered therapeutic advances. The demonstration of increased myeloblasts or clonality or the development of either granulocytic sarcoma or acute myeloid leukemia helps clarify the origin of some cases of chronic eosinophilic leukemia. 1 In a subset of patients, hypereosinophilia is related to excessive secretion of eosinophilopoietic cytokines from a clonal population of lymphocytes. 2 The identification of FIP1-like-1-platelet-derived growth factor receptor-␣ (FIP1L1-PDGFRA) in cases of HES/CEL adds to a growing list of activated fusion tyrosine kinases linked to the pathogenesis of chronic myeloproliferative disorders. 3 It is unique, however, because it is the first description of a gain-of-function fusion protein resulting from a cryptic interstitial deletion between genes rather than a reciprocal chromosomal translocation. The FIP1L1-PDGFR␣ fusion protein transforms hematopoietic cells, and its kinase activity is inhibited by imatinib at a cellular 50% inhibitory concentration (IC 50 ) 100-fold lower than BCR-ABL. 3 Acquisition of an imatinib resistance mutation in the adenosine triphosphate (ATP)-binding domain of PDGFRA in a relapsed patient previously responsive to imatinib supports a critical role for FIP1L1-PDGFR␣ in the pathogenesis of disease and demonstrates that FIP1L1-PDGFR␣ is the therapeutic target of imatinib. 3 The identification of t...

Hypereosinophilic syndrome: Long-term remission following allogeneic stem cell transplant in spite of transient eosinophilia post-transplant

“…Recent studies have suggested a pivotal role for imatinib mesylate in the treatment of HES [16]. A proportion of patients with HES responded to low doses of imatinib mesylate, although some patients were resistant and the duration of the response is still unknown [16,17]. The rapid response to therapy would make imatinib mesylate an attractive drug to improve the clinical condition of the patient, even of those who plan to proceed to allogeneic stem-cell transplant.…”

Large Apical Thrombus in a Patient with Persistent Heart Failure and Hypereosinophilia: Löffler Endocarditis

“…The patient also showed most of the principal clinical features of Löffler endocarditis, such as weight loss, fever, cough, and congestive heart failure. Since the World Health Organization classification recommends the exclusion of any cause of secondary eosinophilia like malignant or autoimmune diseases, parasitic disease, allergy, or drug reactions in the clinical workup of patients with Löffler endocarditis eosinophilia 13,22 , we explored any other cause that might explain the hypereosinophilia. Stool examinations were negative, and there was no sign of a malignancy, allergy, or drug reaction.…”

Structural Study on Apoptosis of Chronic Eosinophilic Leukemia Cells by Interaction of S100A8 with Splicing Factor, Proline and Glutamine-Rich

“…CEL is mostly caused due to FIP1-like-1 platelet-derived growth factor-alpha (FIP1L1-PDGFRa) fusion gene (Gotlib et al, 2004). Eosinophils include a variety of granulocytes, such as neutrophils and basophils, with granules and polymorphous nuclei; they account for approximately 1% to 5% of white blood cells (<1,500/µL) in normal individuals.…”