Gene Summary

Gene:FIP1L1; factor interacting with PAPOLA and CPSF1
Aliases: Rhe, FIP1, hFip1
Summary:This gene encodes a subunit of the CPSF (cleavage and polyadenylation specificity factor) complex that polyadenylates the 3' end of mRNA precursors. This gene, the homolog of yeast Fip1 (factor interacting with PAP), binds to U-rich sequences of pre-mRNA and stimulates poly(A) polymerase activity. Its N-terminus contains a PAP-binding site and its C-terminus an RNA-binding domain. An interstitial chromosomal deletion on 4q12 creates an in-frame fusion of human genes FIP1L1 and PDGFRA (platelet-derived growth factor receptor, alpha). The FIP1L1-PDGFRA fusion gene encodes a constitutively activated tyrosine kinase that joins the first 233 amino acids of FIP1L1 to the last 523 amino acids of PDGFRA. This gene fusion and chromosomal deletion is the cause of some forms of idiopathic hypereosinophilic syndrome (HES). This syndrome, recently reclassified as chronic eosinophilic leukemia (CEL), is responsive to treatment with tyrosine kinase inhibitors. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:pre-mRNA 3'-end-processing factor FIP1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
LeukaemiaFIP1L1-PDGFRA fusion in Leukemia
Fusions of the FIP1L1 and PDGFRA genes are reported in acute myeloid leukemia, T-cell lymphoblastic lymphoma, chronic eosinophilic leukemia - all with eosinophilia (Bain, 2010). Cools et al (2003) reported that many examples of what had previously been categorized as idiopathic hypereosinophilic syndrome were actually chronic eosinophilic leukemia - and that this condition with the FIP1L1-PDGFRA fusion is sensitive to treatments with tyrosine kinase inhibitors such as imatinib. Most FIP1L1-PDGFRA fusions are caused by a cryptic deletion: del(4)(q12), but occasionally by other rearrangements such as translocations t(1;4)(q44;q12)6 and t(4;10)(q12;p11).
View Publications78
-FIP1L1-PDGFRA Fusions in Myeloid Sarcoma
Myeloid sarcoma (aka granulocytic sarcoma) is a rare extramedullary tumor of immature granulocytic cells, usually accompanied by or following acute myeloid leukemia (Yilmaz et al, 2013). The fusion if the FIP1L1-PDGFRA genes is reported in some meyloid sarcomas.
View Publications7

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FIP1L1 (cancer-related)

Moustaka K, Maleskou E, Lambrianidou A, et al.
Docosahexaenoic Acid Inhibits Proliferation of EoL-1 Leukemia Cells and Induces Cell Cycle Arrest and Cell Differentiation.
Nutrients. 2019; 11(3) [PubMed] Free Access to Full Article Related Publications
Τhe effect of docosahexaenoic acid (DHA, an omega-3 polyunsaturated fatty acid) upon the proliferation of EoL-1 (Eosinophilic leukemia) cell line was assessed, while additional cellular events during the antiproliferative action were recorded. DHA inhibited EoL-1 cells growth dose-dependently by inducing growth arrest at G0/1 phase of the cell cycle. After DHA addition to the cells, the expression of

Samarghandi A, Ahuja S, Jindal V, et al.
Hypereosinophilic syndrome preceding a diagnosis of B-cell lymphoma.
Tumori. 2018; 104(6):NP22-NP24 [PubMed] Related Publications
INTRODUCTION: Hypereosinophilic syndrome (HES) is a rare condition characterized by eosinophilia and organ destruction secondary to eosinophilic infiltration. The coexistence of primary B-cell lymphoma and hypereosinophilic syndrome is extremely rare. We present a case of HES that preceded the diagnosis of diffuse large B-cell lymphoma.
CASE REPORT: A 70-year-old man presented with a 3-month history of diarrhea and 30-pound weight loss. Complete blood count showed a white blood cell count of 7452/µL with eosinophils of 42% (absolute eosinophil count 3130). Colonoscopy showed eosinophilic infiltrate in the lamina propria and muscularis mucosa. Bone marrow biopsy showed elevated myeloid: erythroid ratio (6:1), increased mature and immature eosinophilic infiltration (10% of nucleated cells). Molecular studies were negative for Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) translocation and PDGFRB and FGFR mutations, indicating nonclonal eosinophilia. Treatment was initiated with prednisone (1 mg/kg) and hydroxyurea 500 mg twice daily. He responded with complete resolution of symptoms. Five months later, the patient presented with right lower quadrant pain. Abdominal/pelvis computed tomography (CT) showed bulky right inguinal lymphadenopathy and biopsy revealed CD10+ diffuse large B-cell lymphoma (DLBCL). Further staging workup showed the stage to be IIB. He received 6 cycles of chemotherapy and involved field radiation therapy. He achieved complete remission.
CONCLUSION: Reviewing the literature indicates only one case of similar presentation with concomitant HES and DLBCL. Eosinophilia is routinely encountered in clinical practice and as such physicians must be aware of the rarer, more malevolent underlying associations of this condition so as to aid early diagnosis and prompt treatment.

Han NN, Li X, Tao L, Zhou Q
Doxorubicin and rhein loaded nanomicelles attenuates multidrug resistance in human ovarian cancer.
Biochem Biophys Res Commun. 2018; 498(1):178-185 [PubMed] Related Publications
Tumor targeting delivery system has been suggested as an attractive strategy against tumor progression. Combination chemotherapy is essential and effective in preventing ovarian cancer. Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid) is a lipophilic anthraquinone. Emerging evidence indicates that rhein has many pharmacological effects, such as nephroprotective, hepatoprotective, anti-inflammatory, antioxidant, and anticancer activities. In our study, doxorubicin (DOX) and rhein (RHE) co-loaded polymeric micelle (nano-DOX/RHE) were prepared to attenuate drug resistance in ovarian cancer cells while promoting the therapeutic efficiency of DOX. The morphology, particle size (about 25 nm), zeta potential, release profile in vitro, cell proliferation and cytotoxicity effects were calculated. The results suggested that DOX and RHE could be efficiently loaded into micelle nanoparticles, and in vitro study indicated that they could be released from the nanoparticles in an extended period into DOX-resistant SKOV3 cells (SKOV3/DOX). Nano-DOX/RHE exerted an enhanced cytotoxicity and high apoptosis-inducing activities in SKOV3/DOX cells. Importantly, nano-DOX/RHE exhibited better cancer targeting ability, enhancing the anti-tumor efficacy with little toxicity. In conclusion, nano-DOX/RHE promoted the drug target on tumor site with preferable anti-tumor effects, which could be a promising therapeutic strategy against human ovarian cancer.

Helbig G
Imatinib for the treatment of hypereosinophilic syndromes.
Expert Rev Clin Immunol. 2018; 14(2):163-170 [PubMed] Related Publications
INTRODUCTION: Hypereosinophilic syndromes (HES) encompass a group of disorders defined by sustained peripheral blood hypereosinophilia >1500/mm

Zhang L, Liu Y, Wang M, et al.
EZH2-, CHD4-, and IDH-linked epigenetic perturbation and its association with survival in glioma patients.
J Mol Cell Biol. 2017; 9(6):477-488 [PubMed] Free Access to Full Article Related Publications
Glioma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase (IDH) mutations in up to 80% lower grade gliomas (LGG) and in 76% secondary glioblastomas (GBM). IDH mutations are also seen in 10%-20% of acute myeloid leukemia (AML). In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells (pre-LSCs) stage, whereas mutations in genes propagating oncogenic signal are late events in leukemia. IDH mutations are also early events in glioma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in glioma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD4 as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK4, FIP1L1, or FUBP1 collaborate with IDH mutations to negatively affect patients' survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4 at genetic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and glioma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premalignant stem cells to glioma.

Ahmed T, Nawaz S, Noreen R, et al.
A 3' untranslated region polymorphism rs2304277 in the DNA repair pathway gene OGG1 is a novel risk modulator for urothelial bladder carcinoma.
Ann Hum Genet. 2018; 82(2):74-87 [PubMed] Related Publications
Altered DNA repair capacity may affect an individual's susceptibility to cancers due to compromised genomic integrity. This study was designed to elucidate the association of selected polymorphisms in DNA repair genes with urothelial bladder carcinoma (UBC). OGG1 rs1052133 and rs2304277, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs2228001, and XPD rs13181 were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 200 UBC cases and 200 controls. We found association of OGG1 rs2304277 [odds ratio (OR)

Oberley MJ, Denton C, Ji J, et al.
A neoplasm with FIP1L1-PDGFRA fusion presenting as pediatric T-cell lymphoblastic leukemia/lymphoma without eosinophilia.
Cancer Genet. 2017; 216-217:91-99 [PubMed] Related Publications
The 2016 World Health Organization (2016 WHO) classification of hematopoietic malignancies classifies neoplasms with a fusion between the FIP1L1 and PDGFRA genes in 4q12 into a group called "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2". Neoplasms characterized by this fusion are pluripotent stem cell disorders that can show both myeloid and lymphoid differentiation. They typically occur in adult patients and most are characterized by eosinophilia. We describe identification of a FIP1L1-PDGFRA fusion in a 13-year-old boy who presented with T-lymphoblastic leukemia/lymphoma without eosinophilia. Detection of FIP1L1-PDGFRA driven neoplasms at diagnosis is usually critical for proper treatment, since almost all reported cases responded to tyrosine kinase inhibitors. However, our patient's leukemia was refractory to standard chemotherapy, and did not show a meaningful response to tyrosine kinase inhibitor therapy. Testing for a FIP1L1-PDGFRA rearrangement is at present limited to patients with idiopathic hypereosinophilia, and we hypothesize that this abnormality may be under-diagnosed in children with acute leukemias.

Yamamoto M, Ikuta K, Toki Y, et al.
Angioimmunoblastic T-cell lymphoma and hypereosinophilic syndrome with FIP1L1/PDGFRA fusion gene effectively treated with imatinib: A case report.
Medicine (Baltimore). 2017; 96(36):e8001 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and organ damage. Some cases of HES are caused by the FIP1L1/PDGFRA fusion gene and respond to imatinib. FIP1L1/PDGFRA-positive HES occasionally evolves into chronic eosinophilic leukemia or into another form of myeloproliferative neoplasm; however, the development of a malignant lymphoma is very rare. We present a rare case of angioimmunoblastic T-cell lymphoma (AITL) and HES with the FIP1L1/PDGFRA gene rearrangement.
PATIENT CONCERNS: A man in his 30s presented to our hospital with fever, hypereosinophilia, widespread lymphadenopathy, and splenomegaly. Laboratory tests showed hypereosinophilia, increased soluble interleukin-2 receptor, and increased vitamin B12. Positron-emission tomography with F fluorodeoxyglucose (FDG) showed positive FDG uptake in multiple enlarged lymph nodes throughout the body and the red bone marrow. A bone-marrow biopsy showed hypereosinophilia without dysplasia and an increased number of blasts. The FIP1L1/PDGFRA fusion gene was positive upon fluorescence in situ hybridization (FISH) analysis of the peripheral blood. Furthermore, biopsy of a lymph node from the neck revealed restiform hyperplasia of capillary vessels, with small lymphoma cells arranged around the capillaries. Lymphoma cells were positive for CD3, CD4, and CD10, and negative for CD20. Lymphoma cells were also positive for the FIP1L1/PDGFRA fusion gene by FISH analysis.
DIAGNOSES: From these findings, the patient was diagnosed with HES and AITL with FIP1L1/PDGFRA.
INTERVENTIONS: After the diagnosis, corticosteroid was administered but was ineffective. Imatinib was then administered.
OUTCOMES: Imatinib was very effective for treating HES and AITL, and complete remission was achieved in both.
LESSONS: This report presents the first case in which the FIP1L1/PDGFRA fusion gene was positive both in peripheral blood and lymph nodes, implying the possibility that the tumor cells acquired the FIP1L1/PDGFRA fusion gene in the early stage of hematopoietic progenitor cell developments. Imatinib was very effective in treating both HES and lymphoma, suggesting that the FIP1L1/PDGFRA fusion gene plays a key role in the pathogenesis of both HES and lymphoma.

Gotlib J
Tyrosine Kinase Inhibitors in the Treatment of Eosinophilic Neoplasms and Systemic Mastocytosis.
Hematol Oncol Clin North Am. 2017; 31(4):643-661 [PubMed] Related Publications
The World Health Organization's semimolecular classification of eosinophilias emphasizes neoplasms driven by fusion tyrosine kinases. More than 80% of patients with systemic mastocytosis carry the KIT D816V mutation, the primary driver of disease pathogenesis. Genetic annotation of these diseases is critical and affords opportunities for targeted therapy. This article discusses our understanding of the mutated tyrosine kinome of eosinophilic neoplasms and systemic mast cell disease, and the successes and limitations of available therapies. Use of tyrosine kinase inhibitors as a bridge to hematopoietic stem cell transplantation, and development of more selective and potent tyrosine kinase inhibitors is also highlighted.

Appiah-Kubi K, Lan T, Wang Y, et al.
Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies.
Crit Rev Oncol Hematol. 2017; 109:20-34 [PubMed] Related Publications
PURPOSE: To investigate oncogenic platelet-derived growth factor receptor(PDGFR) fusion genes involvement in hematological malignancies, the advances in the PDGFR fusion genes diagnosis and development of PDGFR fusions inhibitors.
METHODS: Literature search was done using terms "PDGFR and Fusion" or "PDGFR and Myeloid neoplasm" or 'PDGFR and Lymphoid neoplasm' or "PDGFR Fusion Diagnosis" or "PDGFR Fusion Targets" in databases including PubMed,, and Medscape.
RESULTS: Out of the 36 fusions detected, ETV6(TEL)-PDGFRB and FIP1L1-PDGFRA fusions were frequently detected, 33 are as a result of chromosomal translocation, FIP1L1-PDGFRA and EBF1-PDGFRB are the result of chromosomal deletion and CDK5RAP2- PDGFRΑ is the result of chromosomal insertion. Seven of the 34 rare fusions have detectable reciprocals.
CONCLUSION: RNA aptamers are promising therapeutic target of PDGFRs and diagnostic tools of PDGFRs fusion genes. Also, PDGFRs have variable prospective therapeutic strategies including small molecules, RNA aptamers, and interference therapeutics as well as development of adaptor protein Lnk mimetic drugs.

Roufosse F, Heimann P, Lambert F, et al.
Severe Prolonged Cough as Presenting Manifestation of FIP1L1-PDGFRA+ Chronic Eosinophilic Leukaemia: A Widely Ignored Association.
Respiration. 2016; 91(5):374-9 [PubMed] Related Publications
Chronic eosinophilic leukaemia associated with the FIP1L1-PDGFRA fusion gene (F/P+ CEL) is a rare cause of marked persistent hypereosinophilia, arising almost exclusively in male patients. Clinical presentations are heterogeneous with a higher incidence of eosinophil-mediated cardiomyopathy than in other hypereosinophilic syndrome variants. Features of chronic myeloproliferative disease are often present, including splenomegaly and elevated serum vitamin B12 levels. The diagnosis is made by fluorescence in situ hybridization (FISH) showing the deletion of the CHIC2 locus and/or RT-PCR showing the FIP1L1-PDGFRA fusion transcript. Treatment with imatinib mesylate, a tyrosine kinase inhibitor, results in rapid and complete resolution of hypereosinophilia and associated symptoms, except for those related to sub-endocardial fibrosis that may be irreversible. We report the case of a male patient in whom isolated intractable cough remained the only clinical manifestation of F/P+ CEL for 4 years. Furthermore, eosinophil autofluorescence, an as yet unreported artefact in this setting, precluded the detection of the CHIC2 deletion and further delayed diagnosis, underlining that both FISH and RT-PCR should be performed when this disease is suspected.

Qu SQ, Qin TJ, Xu ZF, et al.
Long-term outcomes of imatinib in patients with FIP1L1/ PDGFRA associated chronic eosinophilic leukemia: experience of a single center in China.
Oncotarget. 2016; 7(22):33229-36 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The FIP1L1/PDGFRA (F/P) fusion gene is the most common clonal genetic abnormality of chronic eosinophilic leukemia (CEL). Tyrosine kinase inhibitors (TKI), such as imatinib, have been demonstrated to be effective therapies for F/P mutated disease. The aim of this study was to analyze the treatment response and long term prognosis in patients with F/P mutated CEL.
METHODS: The clinical features and treatment responses of 33 consecutive patients with F/P mutated CEL between August 2006 and October 2014 were analyzed. The 33 cases received imatinib therapy at an initial dose of 100 mg/day (30 patients) or 200 mg/day (3 patients); the maintenance dose depended on the response condition and patient willingness. Through the follow up, the molecular responses were regularly monitored.
RESULTS: With a median follow up of 64 months, 94% of the 33 patients with F/P mutated CEL achieved a complete hematologic remission (CHR), and 97% achieved a complete molecular remission (CMR) after a median of 3 (1.5-12) months. Twenty-four cases received maintenance therapy, with a median CMR duration of 43 (5-88) months. Imatinib therapy was discontinued in 8 cases, including 4 cases who experienced relapse, and 4 patients who maintained CHR or CMR after discontinuing therapy with a median time of 47 (2-74) months. One case exhibited primary resistance with a PDGFRA T674I mutation.
CONCLUSIONS: F/P mutated CEL has an excellent long-term prognosis following imatinib therapy. A 100 mg daily dose of imatinib is sufficient to induce remission, and a single 100 mg weekly dose maintains a durable remission. A subgroup of patients may maintain a durable remission after discontinuing therapy with a CMR.

Maack A, Pegard A
Populus nigra (Salicaceae) absolute rich in phenolic acids, phenylpropanoïds and flavonoids as a new potent tyrosinase inhibitor.
Fitoterapia. 2016; 111:95-101 [PubMed] Related Publications
The purpose of this study was to evaluate the tyrosinase inhibitory capacity of Populus nigra buds absolute (PBA) and compare it to kojic acid (KA), controversial reference tyrosinase inhibitor. Populus nigra buds were extracted with hexane and ethanol to obtain PBA. The inhibitory effect of this absolute was first tested on the mushroom Agaricus bisporus tyrosinase. Then the depigmenting potential of PBA was tested on B16F10 murine melanocytes by assaying the activity of tyrosinase and melanin content. Consecutively, a microscopic analysis of intracellular melanin granules was performed. Finally, melanised reconstructed human epidermis (RHE) were used to assess the lightening potential activity of this PBA on human skin. Results show that PBA inhibits A. bisporus tyrosinase (IC50=77±8ppm) and inhibits melanocytes B16F10 tyrosinase (IC50=27±1ppm). PBA decreases intracellular melanin levels, with 50% loss at 39±9ppm. Finally, PBA at 1000ppm lightens RHE and decreases their melanin content of 20%. PBA is a strong inhibitor of tyrosinase and reduces melanogenesis in melanocytes B16F10. Thus, PBA has potential applications in skin-lightening cosmetics.

Roufosse F
Management of Hypereosinophilic Syndromes.
Immunol Allergy Clin North Am. 2015; 35(3):561-75 [PubMed] Related Publications
The symptomatic hypereosinophilic patient must be approached in a stepwise manner, with thorough assessment to determine whether the hypereosinophilia itself is contributing to damage and disease manifestations (thereby defining a hypereosinophilic syndrome), and to identify an eventual cause of hypereosinophilia, followed by initiation of treatment directed against the underlying condition or deleterious hypereosinophilic state. Situations encountered in the clinic are extremely heterogeneous because of the numerous potential causes of hypereosinophilia and the variable spectrum of eosinophil-mediated organ damage. A practical approach to many of these situations is presented in this review.

Zhou J, Papenhausen P, Shao H
Therapy-related acute myeloid leukemia with eosinophilia, basophilia, t(4;14)(q12;q24) and PDGFRA rearrangement: a case report and review of the literature.
Int J Clin Exp Pathol. 2015; 8(5):5812-20 [PubMed] Free Access to Full Article Related Publications
The myeloid and lymphoid neoplasms with eosinophilia and PDGFRA gene rearrangements usually show a good response to Imatinib and are typically associated with a normal karyotype, occasionally exhibiting a secondary chromosomal abnormality associated with clonal evolution. Five variant translocations involving PDGFRA have been reported. Here, we report a rare case of therapy-related acute myeloid leukemia with PDGFRA rearrangement after chemotherapy for prior B lymphoblastic leukemia (B-ALL). The patient had a history of BCR-ABL negative, hypodiploid B-ALL in complete remission after chemotherapy. However, 15 months later the patient developed acute myeloid leukemia with rapidly increasing eosinophilia, basophilia and a complex karyotype that included a novel t(4;14)(q12;q24). FIP1L1 was not associated with the PDGFRA rearrangement. The patient had a very aggressive clinical course, and died from the disease shortly after diagnosis. This is the first case of a primary therapy-related myeloid neoplasm with secondary PDGFRA rearrangement. The t(4:14)(q12;q24) is joining the growing list of the variant translocations involving PDGFRA.

Marton I, Pósfai É, Annus JK, et al.
Ideggyogy Sz. 2015; 68(5-6):212-6 [PubMed] Related Publications
INTRODUCTION: The FIP1L1-PDGFR alpha-positive, hypereosinophilic syndrome (HES) is a new category of hematological entities. Various clinical symptoms may occur, with no specific characteristics in either the clinical picture or the neuroimaging findings, and this may give rise to a diagnostic dilemma. A report on a long follow-up period (10 years) in a case of HES that presented with neuropsychiatric symptoms appears to be unique. Besides the complexity of the diagnostic process, the successful treatment is discussed.
CASE REPORT: The HES was diagnosed in a male patient at the age of 33 years, with involvement of the central nervous system and the myocardium. After the onset of the clinical signs, the MRI indicated bilateral cerebral and cerebellar cortico-subcortical lesions involving the watershed areas, mainly in the parieto-occipital regions. High-dose intravenous steroid (methylprednisolone 500 mg/day) alleviated the neurological symptoms within a few weeks, and the administration of imatinib (200 mg/day) resulted in an impressive regression of the hypereosinophilia and splenomegaly within 6 weeks. During the follow-up, the patient has continued to receive imatinib. The molecular remission has persisted, no new complaints have developed and the condition of the patient has remained stable.
CONCLUSION: The timely recognition of the HES and identification of the disease subtype which led to the administration of imatinib may be the key to successful treatment. The long stable follow-up period gives rise to a new dilemma in the treatment of the HES in these special cases: for how long should a patient receive a tyrosine kinase inhibitor, and may the treatment be suspended?

Schwaab J, Umbach R, Metzgeroth G, et al.
KIT D816V and JAK2 V617F mutations are seen recurrently in hypereosinophilia of unknown significance.
Am J Hematol. 2015; 90(9):774-7 [PubMed] Related Publications
Myeloproliferative neoplasms with eosinophilia are commonly characterized by a normal karyotype and remain poorly defined at the molecular level. We therefore investigated 426 samples from patients with hypereosinophilia of unknown significance initially referred for screening of the FIP1L1-PDGFRA (FP) fusion gene also for KIT D816V and JAK2 V617F mutations. Overall, 86 (20%) patients tested positive: FP+ in 55 (12%), KIT D816V+ in 14 (3%), and JAK2 V617F+ in 17 (4%) patients, respectively. To gain better insight into clinical characteristics, we compared these cases with 31 additional and well-characterized KIT D816V+ eosinophilia-associated systemic mastocytosis (SM-eo) patients enrolled within the "German Registry on Disorders of Eosinophils and Mast cells." Significant differences included younger age, male predominance, and higher eosinophil counts for FP+ cases while abdominal lymphadenopathy, ascites, and serum tryptase levels >100 μg/l were characteristic for those with KIT D816V. Leukocytes, hemoglobin, and splenomegaly did not differ significantly. A median of three additional mutations, most frequently TET2 and SRSF2, were identified in 12/13 KIT D816V+ SM-eo patients with available material indicating a more complex molecular pathogenesis. Median survival was not reached for FP+ cases but was only 26 and 41 months for KIT D816V+ SM and JAK2 V617F+ MPN-eo, respectively. Eosinophilia of ≥2 × 10(9) /l was identified as discriminator for inferior survival in KIT D816V+ and/or JAK2 V617F+ patients (median survival 20 months vs. not reached, P = 0.002). Thus, there is a clear prognostic and therapeutic rationale for detection of KIT D816V and JAK2 V617F in the diagnostic work up of eosinophilia.

Ziegler B, Peitsch WK, Reiter A, et al.
Generalized Eruptive Histiocytosis Associated With FIP1L1-PDGFRA-Positive Chronic Eosinophilic Leukemia.
JAMA Dermatol. 2015; 151(7):766-9 [PubMed] Related Publications
IMPORTANCE: Generalized eruptive histiocytosis (GEH) is a rare non-Langerhans cell histiocytosis with a benign, self-healing course. Neoplastic hematologic disorders of the myeloid lineage have been reported in association with GEH in 4 patients. A clonal association between GEH and the underlying leukemia was suspected in these patients but could only be confirmed in one patient.
OBSERVATIONS: A male patient in his 20s presented with asymptomatic red to brown macules and papules. A skin biopsy confirmed a diagnosis of GEH. His blood cell count revealed hypereosinophilia. Morphologic and molecular analyses from bone marrow and blood samples revealed FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. The patient was treated with imatinib and achieved complete clinical remission of his leukemia and the GEH.
CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of a patient with GEH associated with FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Generalized eruptive histiocytosis in association with a myeloid neoplasm may occur in 2 variants: a reactive condition or a clonal derivative of the underlying leukemia. In this case, both diseases responded well after initiation of treatment with imatinib.

Lekovic D, Bogdanovic A, Perunicic-Jovanovic M, et al.
Diagnostic challenges during pretreatment long-term follow-up in a patient with FIP1L1-PDGFRA-positive eosinophilia.
Intern Med. 2015; 54(6):637-42 [PubMed] Related Publications
Obtaining a precise characterization of eosinophilia is crucial, as successful treatment relies on the underlying etiology of the disease. Platelet-derived growth factor receptor alpha-related disorders were first specified in 2008 as a distinct group of clonal eosinophilic disorders with exceptional responsiveness to imatinib. We herein present the case of a man with myeloid neoplasm and eosinophilia in whom a definitive diagnosis could not be adequately made based on histopathological features who was ultimately diagnosed only after extensive molecular analyses and successfully treated with imatinib. In addition, we discuss the diagnostic and therapeutic approaches to treating patients presenting with eosinophilia.

Shen Y, Ren X, Ding K, et al.
Antitumor activity of S116836, a novel tyrosine kinase inhibitor, against imatinib-resistant FIP1L1-PDGFRα-expressing cells.
Oncotarget. 2014; 5(21):10407-20 [PubMed] Free Access to Full Article Related Publications
The FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) fusion oncogene is the driver factor in a subset of patients with hypereosinophilic syndrome (HES)/chronic eosinophilic leukemia (CEL). Most FIP1L1-PDGFRα-positive patients respond well to the tyrosine kinase inhibitor (TKI) imatinib. Resistance to imatinib in HES/CEL has been described mainly due to the T674I mutation in FIP1L1-PDGFRα, which is homologous to the imatinib-resistant T315I mutation in BCR-ABL. Development of novel TKIs is imperative to overcome resistance to imatinib. We synthesized S116836, a novel TKI. In this study, we evaluated the antitumor activity of S116836 in FIP1L1-PDGFRα-expressing cells. The results showed that S116836 potently inhibited PDGFRα and its downstream signaling molecules such as STAT3, AKT, and Erk1/2. S116836 effectively inhibited the growth of the WT and T674I FIP1L1-PDGFRα-expressing neoplastic cells in vitro and in nude mouse xenografts. Moreover, S116836 induced intrinsic pathway of apoptosis as well as the death receptor pathway, coincided with up-regulation of the proapoptotic BH3-only protein Bim-EL through the Erk1/2 pathway. In conclusion, S116836 is active against WT and T674I FIP1L1-PDGFRα-expressing cells, and may be a prospective agent for the treatment of HES/CEL.

Kempf W, Kazakov DV, Szep Z, Vanecek T
CD30+ clonal T-cell lymphoid proliferation of the skin in a patient with hypereosinophilic syndrome.
J Cutan Pathol. 2015; 42(2):130-5 [PubMed] Related Publications
We report a hitherto undescribed unusual CD30+ clonal T-cell proliferation in a 46-year-old man with the lymphocytic variant of hypereosinophilic syndrome with a 17-year history of pruritus, generalized persistent papulonodular skin lesions and peripheral blood hypereosinophilia. A skin biopsy showed an eosinophil-rich infiltrate with small to medium-sized CD30+ lymphocytes and Churg-Strauss granulomas. Peripheral blood flow cytometry revealed an aberrant T-cell clone which, molecular genetically, was identical to the T-cell clone detected in the skin. No genetic aberrations of platelet-derived growth factor receptor alpha (PDGFRA), FIP1L1-PDGFRA, PDGFRB or FGFR1 were found. The skin lesions showed transient response to systemic and topical corticosteroids. The skin lesions represent cutaneous involvement by clonal T-cells in hypereosinophilic syndrome and differ from known cutaneous CD30+ lymphoproliferative disorders.

Jacobsen E, Pozdnyakova O, Redd R, et al.
Imatinib mesylate lacks efficacy in relapsed/refractory peripheral T cell lymphoma.
Leuk Lymphoma. 2015; 56(4):993-8 [PubMed] Related Publications
Platelet derived growth factor-α (PDGFR-α) is expressed in peripheral T cell lymphoma, not otherwise specified (PTCL, NOS). Imatinib mesylate demonstrated in vitro cytotoxicity against primary PTCL, NOS cells. We initiated a trial of imatinib in 12 patients with relapsed or refractory T-cell non-Hodgkin lymphoma (T-NHL). PDGFR-α expression by immunohistochemistry and fluorescence in situ hybridization (FISH) to assess for FIP1L1-PDGFR-α fusion and/or PDGFR-α amplification were not required for study entry. We documented no objective responses. The median progression-free survival was 21.0 days (90% confidence interval [CI] 15.0, 28.0) and median overall survival was 154 days (90% CI 35, 242). Four patients had tissue available for analysis of PDGFR-α by immunohistochemistry and three of these patients' tumors expressed PDGFR-α. Imatinib was not effective for the treatment of peripheral T cell lymphoma in an unselected group of patients in which PDGFR-α expression was not required for study entry.

Stojsic Z, Brasanac D, Stojanovic M, Boricic M
Cutaneous composite hemangioendothelioma: case report and review of published reports.
Ann Saudi Med. 2014 Mar-Apr; 34(2):182-8 [PubMed] Free Access to Full Article Related Publications
Composite hemangioendothelioma (CHE) is a rare, locally aggressive, vascular tumor of intermediate-/ low-grade malignancy, and is characterized by varying combinations of benign, low-grade malignant, and malignant vascular components. In cutaneous localization, only 22 cases have been reported so far. A new case of CHE of the gluteal region in a 58-year-old man is described. Microscopically, vascular neoplasm, situated mainly within the deep dermis and the subcutaneous fat tissue, was composed of sinusoidal hemangioma, arteriovenous hemangioma, retiform hemangioendothelioma (RHE), and angiosarcoma. An average number of mitoses within the angiosarcomatous component was 10 per 10 high-power fields. Immunohistochemically, the tumor cells were positive for factor VIII-related antigen, CD34, and CD31 and negative for D2-40 and GLUT-1. Ki-67 labeling index was 21%, 1.2%, and 0% in the areas of angiosarcoma, RHE, and sinusoidal hemangioma, respectively. No recurrent disease was noted 3 months after the surgery. The present case displayed the following features previously undescribed in CHE: a novel component of sinusoidal hemangioma and localization at the gluteal region. We also provide review of clinical, histopathological, and immunohistochemical characteristics of cutaneous CHE from the published cases.

Iwasaki J, Kondo T, Darmanin S, et al.
FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia.
Ann Hematol. 2014; 93(9):1473-81 [PubMed] Related Publications
FIP1-like 1 (FIP1L1) is associated with two leukemogenic fusion genes: FIP1L1-retinoic acid receptor alpha (RARA) and FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA). Analyses of a series of deletion mutants revealed that the FIP1 motif in FIP1L1-RARA plays a pivotal role in its homodimerization and transcriptional repressor activity. However, in FIP1L1-PDGFRA, the C-terminal PDGFRA portion possesses the ability of forming a homodimer by itself, making FIP1L1 dispensable for constitutive activation of this kinase. Both the full-length and the C-terminal PDGFRA portion of FIP1L1-PDGFRA could transform the IL-3-dependent hematopoietic cell line, BAF-B03. Moreover, when either the full-length or the C-terminal PDGFRA portion of FIP1L1-PDGFRA was introduced in these cells, they grew in the absence of IL-3. The cells having the C-terminal PDGFRA portion of FIP1L1-PDGFRA, however, were partially IL-3 dependent, whereas the cells having the full-length FIP1L1-PDGFRA became completely IL-3 independent for their growth. Taken together, these results show that FIP1L1 differentially contributes to the pathogenesis of distinct types of leukemia.

Kovalszki A, Weller PF
Eosinophilia in mast cell disease.
Immunol Allergy Clin North Am. 2014; 34(2):357-64 [PubMed] Free Access to Full Article Related Publications
Eosinophils and mast cells coexist in clonal and nonclonal disorders. The interplay between these cells is complex and not fully understood. Discussed are both allergic/nonclonal disorders in which both cell types are increased in number are likely to play a role in pathogenesis and clonal disorders in which both cell types are affected and play key roles in pathogenesis. Finally, some treatment options, keeping both disorders in mind, are discussed. Future directions in thinking about these disorders are also briefly explored.

Shah S, Loghavi S, Garcia-Manero G, Khoury JD
Discovery of imatinib-responsive FIP1L1-PDGFRA mutation during refractory acute myeloid leukemia transformation of chronic myelomonocytic leukemia.
J Hematol Oncol. 2014; 7:26 [PubMed] Free Access to Full Article Related Publications
The FIP1L1-PDGFRA rearrangement results in constitutive activation of the tyrosine kinase PDGFRA. Neoplasms harboring this rearrangement are responsive to imatinib mesylate at doses much lower than those recommended for the treatment of chronic myelogenous leukemia. Only a single report has described the identification of FIP1L1-PDGFRA in chronic myelomonocytic leukemia (CMML). Herein, we present a case report of a patient in whom the FIP1L1-PDGFRA was discovered as he evolved from CMML to acute myeloid leukemia (AML). The presence of a dominant neoplastic clone with FIP1L1-PDGFRA rearrangement was suspected on the basis of sudden onset of peripheral and bone marrow eosinophilia and confirmed by fluorescence in situ hybridization and molecular diagnostic tests. Whereas the patient was initially refractory to chemotherapy before the rearrangement was detected, subsequent therapy with imatinib led to complete remission.

Noël LA, Arts FA, Montano-Almendras CP, et al.
The tyrosine phosphatase SHP2 is required for cell transformation by the receptor tyrosine kinase mutants FIP1L1-PDGFRα and PDGFRα D842V.
Mol Oncol. 2014; 8(3):728-40 [PubMed] Free Access to Full Article Related Publications
Activated forms of the platelet derived growth factor receptor alpha (PDGFRα) have been described in various tumors, including FIP1L1-PDGFRα in patients with myeloproliferative diseases associated with hypereosinophilia and the PDGFRα(D842V) mutant in gastrointestinal stromal tumors and inflammatory fibroid polyps. To gain a better insight into the signal transduction mechanisms of PDGFRα oncogenes, we mutated twelve potentially phosphorylated tyrosine residues of FIP1L1-PDGFRα and identified three mutations that affected cell proliferation. In particular, mutation of tyrosine 720 in FIP1L1-PDGFRα or PDGFRα(D842V) inhibited cell growth and blocked ERK signaling in Ba/F3 cells. This mutation also decreased myeloproliferation in transplanted mice and the proliferation of human CD34(+) hematopoietic progenitors transduced with FIP1L1-PDGFRα. We showed that the non-receptor protein tyrosine phosphatase SHP2 bound directly to tyrosine 720 of FIP1L1-PDGFRα. SHP2 knock-down decreased proliferation of Ba/F3 cells transformed with FIP1L1-PDGFRα and PDGFRα(D842V) and affected ERK signaling, but not STAT5 phosphorylation. Remarkably, SHP2 was not essential for cell proliferation and ERK phosphorylation induced by the wild-type PDGF receptor in response to ligand stimulation, suggesting a shift in the function of SHP2 downstream of oncogenic receptors. In conclusion, our results indicate that SHP2 is required for cell transformation and ERK activation by mutant PDGF receptors.

Uchida T, Kitaura J, Nakahara F, et al.
Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis.
Exp Hematol. 2014; 42(5):369-379.e3 [PubMed] Related Publications
We have previously shown that elevated expression of Hairy enhancer of split 1 (Hes1) contributes to blast crisis transition in Bcr-Abl-positive chronic myelogenous leukemia. Here we investigate whether Hes1 is involved in the development of other myeloid neoplasms. Notably, Hes1 expression was elevated in only a few cases of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two of five samples of Fip1-like1 platelet-derived growth factor receptor-α (FIP1L1-PDGFA)-positive myeloid neoplasms associated with eosinophilia. Whereas FIP1L1-PDGFRα alone induced acute T-cell leukemia or myeloproliferative neoplasms in mouse bone marrow transplantation models, mice transplanted with bone marrow cells expressing both Hes1 and FIP1L1-PDGFRα developed acute leukemia characterized by an expansion of myeloid blasts and leukemic cells without eosinophilic granules. FIP1L1-PDGFRα conferred cytokine-independent growth to Hes1-transduced common myeloid progenitors, interleukin-3-dependent cells. Imatinib inhibited the growth of common myeloid progenitors expressing Hes1 with FIP1L1-PDGFRα, but not with imatinib-resistant FIP1L1-PDGFRα mutants harboring T674I or D842V. In contrast, ponatinib efficiently eradicated leukemic cells expressing Hes1 and the imatinib-resistant FLP1L1-PDGFRΑ mutant in vitro and in vivo. Thus, we have established mouse models of FIP1L1-PDGFRA-positive leukemia in myeloid blast crisis, which will help elucidate the pathogenesis of the disease and develop a new treatment for it.

Barraco D, Carobolante F, Candoni A, et al.
Complete and long-lasting cytologic and molecular remission of FIP1L1-PDGFRA-positive acute eosinophil myeloid leukaemia, treated with low-dose imatinib monotherapy.
Eur J Haematol. 2014; 92(6):541-5 [PubMed] Related Publications
Myeloproliferative neoplasms associated with FIP1L1-PDGFR rearrangements represent a rare subset of myeloid and lymphoid malignancies, characterised by the presence of eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 genes. The fusion product of such genes is a tyrosine kinase oncoprotein sensitive to imatinib, which to date results to be the standard of care for FIP1L1-PDGFRA-positive chronic myeloproliferative disorders with eosinophilia. However, the coexistence of FIP1L1-PDGFRA rearrangement associated with acute myeloid leukaemia is extremely rare. Here, we report a rare case of FIP1L1-PDGFRA-positive acute myeloid leukaemia, with marked peripheral blood and bone marrow eosinophilia, treated with low dose of imatinib monotherapy, achieving a rapid and long-lasting complete cytologic and molecular remission, without need for intensive chemotherapy.

Shen Y, Shi X, Pan J
The conformational control inhibitor of tyrosine kinases DCC-2036 is effective for imatinib-resistant cells expressing T674I FIP1L1-PDGFRα.
PLoS One. 2013; 8(8):e73059 [PubMed] Free Access to Full Article Related Publications
The cells expressing the T674I point mutant of FIP1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRα) in hypereosinophilics syndrome (HES) are resistant to imatinib and some second-generation tyrosine kinase inhibitors (TKIs). There is a desperate need to develop therapy to combat this acquired drug resistance. DCC-2036 has been synthesized as a third-generation TKI to combat especially the Bcr-Abl T315I mutant in chronic myeloid leukemia. This study evaluated the effect of DCC-2036 on FIP1L1-PDGFRα-positive cells, including the wild type (WT) and the T674I mutant. The in vitro effects of DCC-2036 on the PDGFRα signal pathways, proliferation, cell cycling and apoptosis of FIP1L1-PDGFRα-positive cells were investigated, and a nude mouse xenograft model was employed to assess the in vivo antitumor activity. We found that DCC-2036 decreased the phosphorylated levels of PDGFRα and its downstream targets without apparent effects on total protein levels. DCC-2036 inhibited proliferation, and induced apoptosis with MEK-dependent up-regulation of the pro-apoptotic protein Bim in FIP1L1-PDGFRα-positive cells. DCC-2036 also exhibited in vivo antineoplastic activity against cells with T674I FIP1L1-PDGFRα. In summary, FIP1L1-PDGFRα-positive cells are sensitive to DCC-2036 regardless of their sensitivity to imatinib. DCC-2036 may be a potential compound to treat imatinib-resistant HES.

Further References

Cools J, DeAngelo DJ, Gotlib J, et al.
A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.
N Engl J Med. 2003; 348(13):1201-14 [PubMed] Related Publications
BACKGROUND: Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.
METHODS: We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.
RESULTS: Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.
CONCLUSIONS: The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

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