The

new england journal

of

medicine

p er s pect ive

The Hypereosinophilic Syndrome and the Biology of Cancer
Robert S. Schwartz, M.D. Patients with sustained high-grade eosinophilia without an evident cause usually receive the diagnosis of hypereosinophilic syndrome, a high-sounding term that only masks our ignorance. Apart from the consistent presence of hypereosinophilia, the clinical picture of the hypereosinophilic syndrome varies. In some cases, the toxic contents of tissueinvasive eosinophils (see electron micrograph) cause heart failure, pulmonary lesions, and harm to other organs. In other cases, urticaria and itchy nodules in the skin dominate the clinical picture. The hypereosinophilic syndrome is a rare disorder, yet as Cools et al. tell us in this issue of the Journal (pages 1201–1214), it carries a message of general interest concerning the fundamental biology of cancer: chromosomal aberrations that can be detected by standard karyotyping, a common feature of many kinds of neoplasms, is a marker for a cryptic molecular arrangement that has created an oncogenic partnership between two otherwise innocent genes. The production of eosinophils requires three cytokines: interleukin-5, interleukin-3, and granulocyte–macrophage colony-stimulating factor. Cells destined for the eosinophilic lineage display highaffinity receptors for interleukin-5, a specific differentiation factor for eosinophils. In rare instances, lymphoma or leukemia cells overproduce interleukin-5, thereby evoking hypereosinophilia. In most cases of idiopathic hypereosinophilic syndrome, however, the eosinophils are independent of growth factors, and the condition has features of a myeloproliferative syndrome: hepatosplenomegaly, thrombocytopenia, abnormal chromosomes, and clonal populations of eosinophils. In another type of hypereosinophilic syndrome, a monoclonal population of T cells lurks behind the eosinophils. These T cells are activated, display abnormal combinations of surface markers, and produce large amounts of interleukin-5, the presumed cause of the eosinophilia. IgE levels in serum can be very high, perhaps because of other cytokines released by the T cells. Many patients with this variant
n engl j med 348;13

Electron Micrograph of an Eosinophil. The “pince-nez” nucleus is surrounded by granules, many of which have an electron-dense core. This core consists of a highly toxic basic protein. The matrix surrounding the core contains toxic cationic proteins and a peroxidase. (Courtesy of Dr. Janine André-Schwartz.)

of the hypereosinophilic syndrome have an intractable dermatitis. In these cases, the peculiar T cells, especially those with abnormal chromosomes, seem to be headed toward neoplastic transformation. Indeed, biopsies of the dermatitis may show signs suggestive of cutaneous T-cell lymphoma, and frank lymphoma can develop in the lymph nodes. Recently, several groups have reported that some cases of the hypereosinophilic syndrome respond to imatinib mesylate. This is good news, because the syndrome is inexorable and often fatal. Imatinib was originally used to treat chronic myelogenous leukemia, which is caused by a cytogenetic defect termed t(9;22)(q34;q11), in which breaks form in chromosomes 9 and 22, which then exchange chromosomal fragments. This reciprocal translocation (“t”), in which the breaks occur at band q34 on the long arm (“q”) of chromosome 9 and at band q11 of chromosome 22, creates
march 27, 2003

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treated with imatinib. A minute chromosome in human chronic granulocytic leukemia. Nowell PC. Since the BCR-ABL translocation does not occur in the hypereosinophilic syndrome.q12) q12 deletion The Chromosomal Aberration in the Hypereosinophilic Syndrome. FIP1L1-PDGFRA. BCR-ABL. of which the discovery of FIP1L1-PDGFRA is an example.org march 27. The EVT6-PDGFRb fusion protein is a constantly active tyrosine kinase with oncogenic properties and is inhibited by imatinib. The FIP1L1-PDGFRa fusion protein is a plausible cause of some cases of the hypereosinophilic syndrome. laid the foundation for innumerable advances in the molecular genetics of neoplastic diseases. As we prepare to celebrate the 50th anniversary of the discovery of the double-helical structure of DNA. 2013. BCR-ABL. the BCR-ABL fusion protein. The subsequent finding that the “minute chromosome” they described is a reciprocal translocation that results in a leukemogenic protein. By an extraordinary coincidence. The key that unlocked the secret to the molecular lesion was held by a patient with a translocation termed t(1. Whether any of these patients with skin lesions had a monoclonal population of T cells is unknown. FIP1L1. the recent results with imatinib point to a molecular lesion in the disease that results in a new kind of tyrosine kinase. confirm these clinical reports and reveal the nature of the lesion. a plant lectin. For personal use only. the product of PDGFRA. The product of the fusion gene is a constitutively active tyrosine kinase. 2003 The New England Journal of Medicine Downloaded from nejm. PDGFRa. is a tyrosine kinase. Other molecular abnormalities are likely to be found. exemplified by the article by Cools et al. of the four patients with dermatologic manifestations. They are tyrosine kinases.4) (q44. however. it is clear that the union of molecular biology with clinical medicine. Of the 11 patients Cools et al.132:1497. PDGFRb and the PDGFRa involved in the hypereosinophilic syndrome are receptors for members of the platelet-derived growth factor (PDGF) family. Now we can understand the clinical responses of the hypereosinophilic syndrome to imatinib. Cools et al. two had the FIP1L1PDGFRA abnormality. because the con- stitutively active FIP1L1-PDGFRa tyrosine kinase is analogous to the imatinib-sensitive BCR-ABL enzyme. In this lesion. The t(1. they signal cells to proliferate.q12) translocation (Panel A) found in one patient with the disease provided the clue to the oncogenic lesion. 1200 n engl j med 348. The villain emerged when Cools et al. because a search for FIP1L1-PDGFRA in 16 patients with the hypereosinophilic syndrome uncovered it in only 9. This is not a surprising result. whereas the molecular lesion shown in Panel B was present in 9 of 16 patients. and its partner in the fusion protein. Copyright © 2003 Massachusetts Medical Society.q12). given the heterogeneity of the syndrome. 1. All of them had life-threatening manifestations of the hypereosinophilic syndrome. 10 entered complete remission (1 of them only transiently). In 1960. strange genetic bedfellows.org on November 15. Hungerford DA. keeps PDGFRa continuously active. Science 1960. Nowell and Hungerford1 used this phenomenon to discover the Philadelphia chromosome of chronic myelogenous leukemia.nejm. triggers the division of mammalian cells in vitro. deletion of a region in the long arm of chromosome 4 (q12) was repaired by the joining of pieces of two genes. . especially in view of its oncogenic properties in vitro. What remains to be solved is the problem of how these growth factor receptors relate to hypereosinophilia. which fused to form a novel gene. and when ligated by the corresponding growth factor. Interestingly.13 www. is a ceaselessly active enzyme (a tyrosine kinase) that is sensitive to suppression by imatinib. It fuses pieces of DNA from two genes. BCR and ABL. FIP1L1 and PDGFRA.. Also notable is the previously reported fusion gene involving PDGFRB (EVT6-PDGFRB) that has been found in patients with certain chronic myeloproliferative diseases with high-grade eosinophilia. found that a deletion of chromosomal material from 4q12 had left behind fragments of two genes. The product of the conjoined genes. No other uses without permission.The new england journal of medicine A 1 p 4 B 4 Oncogenic fusion gene PDGFRA q q12 FIP1L1 q44 t(1.4)(q44. PDGFRA and FIP1L1. thus allowing easy visualization of chromosomes.4)(q44. All rights reserved. The discovery of FIP1L1-PDGFRA owes a considerable debt to the simple observation that phytohemagglutinin. is now paying handsome dividends in the clinic. as shown in the diagram (see Figure). forming a new gene. a specific inhibitor of several tyrosine kinases. This translocation was not found in any other patient with the hypereosinophilic syndrome.