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Jan Cools - One of the best experts on this subject based on the ideXlab platform.
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recent breakthroughs in the understanding and management of chronic Eosinophilic Leukemia
Expert Review of Anticancer Therapy, 2009Co-Authors: Els Lierman, Jan CoolsAbstract:The term hyperEosinophilic syndrome (HES) was initially introduced to describe a group of diseases all characterized by persistent unexplained hypereosinophilia. Additional names have subsequently been introduced to describe specific variants of HES, such as the myeloid variant and the lymphoid variant, or to indicate idiopathic HES, for which the cause of the eosinophilia is completely unknown. Molecular analysis led to the identification of the clonal origin of several subgroups of HES, clearly establishing these diseases as true Leukemias. These cases of hypereosinophilia are now referred to as 'myeloid neoplasms associated with eosinophilia and abnormalities of PDGF receptor A and B (PDGFRA and PDGFRB), or FGF receptor 1 (FGFR1)'. In cases for which clonality is clear, but no PDGFRA, PDGFRB or FGFR1 rearrangement could be demonstrated, the term 'chronic Eosinophilic Leukemia, not otherwise specified' is preferred. Most importantly, patients with rearrangements of PDGFRA or PDGFRB can be efficiently treated with the kinase inhibitor imatinib. Additional potent kinase inhibitors have been identified, also including inhibitors that target FGFR1 and imatinib-resistant variants of PDGFRalpha. For treatment of unexplained hypereosinophilia and 'chronic Eosinophilic Leukemia, not otherwise specified; different therapeutic strategies are currently under investigation and promising results have been obtained using humanized anti-IL-5 antibodies. Further molecular understanding of the cause of these 'idiopathic' diseases may lead to the development of novel targeted therapies.
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fip1l1 pdgfr alpha d842v a novel panresistant mutant emerging after treatment of fip1l1 pdgfr alpha t674i Eosinophilic Leukemia with single agent sorafenib
Leukemia, 2009Co-Authors: Els Beullens, Jan Cools, Els Lierman, Peter Marynen, Lucienne Michaux, Pascal Pierre, Peter VandenbergheAbstract:Chronic Eosinophilic Leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions or other genetic lesions. Most FIP1L1–PDGFRA positive patients enjoy durable and complete molecular responses to low-dose imatinib (Glivec/Gleevec). However, resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease, and sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, is active against this mutant in vitro. We describe a case of FIP1L1-PDGFRα T674I CEL in blast crisis that responded to sorafenib (Nexavar). However, this clinical response was short-lived because of the rapid emergence of a FIP1L1-PDGFRα D842V mutant. An N-Nitroso-N-ethylurea-mutagenesis screen indeed identified this mutant as a major sorafenib-resistant mutant. In vitro, the novel FIP1L1-PDGFRα D842V mutant is highly resistant to sorafenib, imatinib, dasatinib (Sprycell) and PKC412 (Midostaurin). Thus, sorafenib is clinically active in imatinib-resistant FIP1L1-PDGFRα T674I CEL, but the rapid emergence of other mutants may limit the response duration. The identification of new PDGFR inhibitors will be required to overcome resistance by this D842V mutant.
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FIP1L1-PDGFRα D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRα T674I Eosinophilic Leukemia with single agent sorafenib
Leukemia, 2009Co-Authors: Els Lierman, Jan Cools, Peter Marynen, Lucienne Michaux, Pascal Pierre, Els Beullens, J Cools, Peter VandenbergheAbstract:Chronic Eosinophilic Leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions or other genetic lesions. Most FIP1L1–PDGFRA positive patients enjoy durable and complete molecular responses to low-dose imatinib (Glivec/Gleevec). However, resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease, and sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, is active against this mutant in vitro. We describe a case of FIP1L1-PDGFRα T674I CEL in blast crisis that responded to sorafenib (Nexavar). However, this clinical response was short-lived because of the rapid emergence of a FIP1L1-PDGFRα D842V mutant. An N -Nitroso- N -ethylurea-mutagenesis screen indeed identified this mutant as a major sorafenib-resistant mutant. In vitro, the novel FIP1L1-PDGFRα D842V mutant is highly resistant to sorafenib, imatinib, dasatinib (Sprycell) and PKC412 (Midostaurin). Thus, sorafenib is clinically active in imatinib-resistant FIP1L1-PDGFRα T674I CEL, but the rapid emergence of other mutants may limit the response duration. The identification of new PDGFR inhibitors will be required to overcome resistance by this D842V mutant.
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FIP1L1-PDGFRA in chronic Eosinophilic Leukemia and BCR-ABL1 in chronic myeloid Leukemia affect different leukemic cells.
Leukemia, 2007Co-Authors: Barbara Crescenzi, Peter Vandenberghe, Andrew Chase, R La Starza, Donatella Beacci, Vittorio Rosti, Anna Gallì, Giorgina Specchia, M. F. Martelli, Jan CoolsAbstract:We investigated genetically affected leukemic cells in FIP1L1-PDGFRA+ chronic Eosinophilic Leukemia (CEL) and in BCR-ABL1+ chronic myeloid Leukemia (CML), two myeloproliferative disorders responsive to imatinib. Fluorescence in situ hybridization specific for BCR-ABL1 and for FIP1L1-PDGFRA was combined with cytomorphology or with lineage-restricted monoclonal antibodies and applied in CML and CEL, respectively. In CEL the amount of FIP1L1-PDGFRA+ cells among CD34+ and CD133+ cells, B and T lymphocytes, and megakaryocytes were within normal ranges. Positivity was found in eosinophils, granulo-monocytes and varying percentages of erythrocytes. In vitro assays with imatinib showed reduced survival of peripheral blood mononuclear cells but no reduction in colony-forming unit growth medium (CFU-GM) growth. In CML the BCR-ABL1 fusion gene was detected in CD34+/CD133+ cells, granulo-monocytes, eosinophils, erythrocytes, megakaryocytes and B-lymphocytes. Growth of both peripheral blood mononuclear cells and CFU-GM was inhibited by imatinib. This study provided evidence for marked differences in the leukemic masses which are targeted by imatinib in CEL or CML, as harboring FIP1L1-PDGFRA or BCR-ABL1.
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Detection of the FIP1L1-PDGFRA fusion in idiopathic hyperEosinophilic syndrome and chronic Eosinophilic Leukemia.
Methods in molecular medicine, 2006Co-Authors: Elizabeth H Stover, Jan Cools, D. Gary GillilandAbstract:Idiopathic hyperEosinophilic syndrome (HES) and chronic Eosinophilic Leukemia (CEL) are related hematological malignancies characterized by sustained, unexplained hypereosinophilia (>1,500 eosinophils/microL). The term CEL is used when there is evidence that the disease is of clonal origin. We recently identified the FIP1L1-PDGFRA fusion gene in approx 50% of HES/CEL cases. Fusion of FIP1L1 to PDGFRA is the consequence of a deletion on chromosome 4, del(4)(q12q12), with the centromeric breakpoint in FIP1L1 and the telomeric breakpoint in PDGFRA. The breakpoints in FIP1L1 are diverse (introns 7 to 10), but the breakpoints in PDGFRA are always in exon 12 (encoding the juxtamembrane region). Because the chromosomal deletion is only 800 kb in size, it remains undetected with standard cytogenetics. In agreement with this, most patients with HES/CEL present with a normal karyotype. Here we describe three different techniques to detect the presence of the FIP1L1-PDGFRA fusion gene in peripheral blood or bone marrow cells.
Ji-sook Lee - One of the best experts on this subject based on the ideXlab platform.
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S100A8 and S100A9 Promote Apoptosis of Chronic Eosinophilic Leukemia Cells
Frontiers in immunology, 2020Co-Authors: Ji-sook Lee, Na Rae Lee, Ayesha Kashif, Seung-ju Yang, A. Reum Nam, Ik-chan Song, Soojung Gong, Min Hwa Hong, Geunyeong Kim, Pu Reum SeokAbstract:S100A8 and S100A9 function as essential factors in inflammation, and also exert anti-tumor or tumorigenic activity depending on the type of cancer. Chronic Eosinophilic Leukemia (CEL) is a rare hematological malignancy having elevated levels of eosinophils, and characterized by the presence of the FIP1L1-PDGFRA fusion gene. In this study, we examined the pro-apoptotic mechanisms of S100A8 and S100A9 in FIP1L1-PDGFRα+ Eosinophilic cells and hyperEosinophilic patient cells. S100A8 and S100A9 induce apoptosis of the FIP1L1-PDGFRα+ EoL-1 cells via TLR4. The surface TLR4 expression increased after exposure to S100A8 and S100A9, although total TLR4 expression decreased. S100A8 and S100A9 suppressed the FIP1L1-PDGFRα-mediated signaling pathway by downregulating FIP1L1-PDGFRα mRNA and protein expression, and triggered cell apoptosis by regulating caspase 9/3 pathway and Bcl family proteins. S100A8 and S100A9 also induced apoptosis of imatinib-resistant EoL-1 cells (EoL-1-IR). S100A8 and S100A9 blocked tumor progression of xenografted EoL-1 and EoL-1-IR cells in NOD-SCID mice, and evoked apoptosis of eosinophils derived from hyperEosinophilic syndrome as well as chronic Eosinophilic Leukemia. These findings may contribute to a progressive understanding of S100A8 and S100A9 in the pathogenic and therapeutic mechanism of hematological malignancy.
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the role of s100a8 and s100a9 in differentiation of human Eosinophilic Leukemia cells eol 1
The Bulletin of Symbolic Logic, 2017Co-Authors: In Sik Kim, Ji-sook LeeAbstract:S100A8 and S100A9 are associated with myeloid cell differentiation, chemotactic activities, adhesion of neutrophils, and apoptosis. In this study, we investigated the contribution of S100A8 and S100A9 to differentiation of the human Eosinophilic Leukemia cell line, EoL-1. S100A8 and S100A9 increased the number of vacuole per one cell and the protein expression of EPO and MBP. Rottlerin, an inhibitor of protein kinase C delta (PKCδ), inhibited the EoL-1 cell differentiation induced by S100A8 and S100A9. These results suggest that S100A8 and S100A9 may regulate the differentiation of Eosinophilic progenitors. Moreover, these findings may shed light on elucidation of eosinophil differentiation due to S100 proteins.
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Leukotactin-1/CCL15 induces cell migration and differentiation of human Eosinophilic Leukemia EoL-1 cells through PKCδ activation
Molecular Biology Reports, 2010Co-Authors: Ji-sook LeeAbstract:Leukotactin-1 (Lkn-1)/CCL15 is a CC chemokine that binds to the CCR1 and CCR3. Lkn-1 functions as an essential factor in the migration of monocytes, lymphocytes, and neutrophils. Although eosinophils express both receptors, the role of Lkn-1 in immature eosinophils remains to be elucidated. In this present study, we investigated the contribution of the CCR1-binding chemokines to chemotactic activity and in the differentiation in the human Eosinophilic Leukemia cell line EoL-1. Lkn-1 induced the stronger migration of EoL-1 cells than other CCR1-binding chemokines such as RANTES/CCL5, MIP-1α/CCL3 and HCC-4/CCL16. Lkn-1-induced chemotaxis was inhibited by pertussis toxin, an inhibitor of G_i/G_o protein; U73122, an inhibitor of phospholipase C and rottlerin, an inhibitor of protein kinase C delta (PKCδ). Lkn-1 increased PKCδ activity, which was partially blocked by the pertussis toxin and U73122. Lkn-1 enhanced the butyric acid-induced differentiation via PKCδ after binding to the increased CCR1 because Lkn-1 caused EoL-1 cells to change morphologically into mature eosinophil-like cells. Likewise, Lkn-1 increased the expression of both eosinophil peroxidase (EPO) and the major basic protein (MBP). PKCδ activation due to Lkn-1 is involved in migration, as well as the butyric acid-induced differentiation. This finding contributes to an understanding of CC chemokines in eosinophil biology and to the development of novel therapies for the treatment of Eosinophilic disorders. This study suggests the pivotal roles of Lkn-1 in the regulation of the movement and development of eosinophils.
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the roles of mcp 1 and protein kinase cδ activation in human Eosinophilic Leukemia eol 1 cells
Cytokine, 2009Co-Authors: Ji-sook Lee, Eun Ju YangAbstract:Abstract Idiopathic hypereosinophilc syndrome is a disorder associated with clonally Eosinophilic proliferation. The importance of FIP1-like-1-platelet-derived growth factor receptor-α (FIP1L1-PDGFRA) in the pathogenesis and classification of HES has been recently reported. In this study, we investigated the contribution of monocyte chemoattractant protein-1 (MCP-1)/CCL2 to chemotactic activity and protein kinase C delta (PKCδ in the human Eosinophilic Leukemia cell line EoL-1. These cells express CCR2 protein among the CC chemokine receptors (CCR1-5). MCP-1 induces strong migration of EoL-1 cells and the chemotaxis signal in response to MCP-1 involves a G i /G o protein, phospholipase C (PLC), PKCδ, p38 MAPK and NF-κB. MCP-1 activates p38 MAPK via G i /G o protein, PLC and PKCδ cascade. MCP-1 also induces NF-κB translocation and the activation is inhibited by PKCδ activation. The increase in the basal expression and activity of PKCδ in EoL-1 cells, compared to normal eosinophils, inhibits apoptosis in EoL-1 cells. Anti-apoptotic mechanism of PKCδ is related to inhibition of caspase 3 and caspase 9, but not to FIP1L1-PDGFRA. PKCδ functions as an anti-apoptotic molecule, and is involved in EoL-1 cell movement stimulated by MCP-1. This study contributes to an understanding of MCP-1 in eosinophil biology and pathogenic mechanism of Eosinophilic disorders.
K.n. Leung - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis- and differentiation-inducing activities of jacaric acid, a conjugated linolenic acid isomer, on human Eosinophilic Leukemia EoL-1 cells
Oncology reports, 2014Co-Authors: Wai Nam Liu, K.n. LeungAbstract:Abstract Conjugated linolenic acids (CLNAs) are a group of naturally occurring positional and geometrical isomers of the C18 polyunsaturated essential fatty acid, linolenic acid (LNA), with three conjugated double bonds (C18:3). Although previous research has demonstrated the growth-inhibitory effects of CLNA on a wide variety of cancer cell lines in vitro, their action mechanisms and therapeutic potential on human myeloid Leukemia cells remain poorly understood. In the present study, we found that jacaric acid (8Z,10E,12Z-octadecatrienoic acid), a CLNA isomer which is present in jacaranda seed oil, inhibited the in vitro growth of human Eosinophilic Leukemia EoL-1 cells in a time- and concentration-dependent manner. Mechanistic studies showed that jacaric acid triggered cell cycle arrest of EoL-1 cells at the G0/G1 phase and induced apoptosis of the EoL-1 cells, as measured by the Cell Death Detection ELISAPLUS kit, Annexin V assay and JC-1 dye staining. Notably, the jacaric acid-treated EoL-1 cells also underwent differentiation as revealed by morphological and phenotypic analysis. Collectively, our results demonstrated the capability of jacaric acid to inhibit the growth of EoL-1 cells in vitro through triggering cell cycle arrest and by inducing apoptosis and differentiation of the Leukemia cells. Therefore, jacaric acid might be developed as a potential candidate for the treatment of certain forms of myeloid Leukemia with minimal toxicity and few side effects.
Peter Marynen - One of the best experts on this subject based on the ideXlab platform.
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FIP1L1-PDGFRα D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRα T674I Eosinophilic Leukemia with single agent sorafenib
Leukemia, 2009Co-Authors: Els Lierman, Jan Cools, Peter Marynen, Lucienne Michaux, Pascal Pierre, Els Beullens, J Cools, Peter VandenbergheAbstract:Chronic Eosinophilic Leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions or other genetic lesions. Most FIP1L1–PDGFRA positive patients enjoy durable and complete molecular responses to low-dose imatinib (Glivec/Gleevec). However, resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease, and sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, is active against this mutant in vitro. We describe a case of FIP1L1-PDGFRα T674I CEL in blast crisis that responded to sorafenib (Nexavar). However, this clinical response was short-lived because of the rapid emergence of a FIP1L1-PDGFRα D842V mutant. An N -Nitroso- N -ethylurea-mutagenesis screen indeed identified this mutant as a major sorafenib-resistant mutant. In vitro, the novel FIP1L1-PDGFRα D842V mutant is highly resistant to sorafenib, imatinib, dasatinib (Sprycell) and PKC412 (Midostaurin). Thus, sorafenib is clinically active in imatinib-resistant FIP1L1-PDGFRα T674I CEL, but the rapid emergence of other mutants may limit the response duration. The identification of new PDGFR inhibitors will be required to overcome resistance by this D842V mutant.
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fip1l1 pdgfr alpha d842v a novel panresistant mutant emerging after treatment of fip1l1 pdgfr alpha t674i Eosinophilic Leukemia with single agent sorafenib
Leukemia, 2009Co-Authors: Els Beullens, Jan Cools, Els Lierman, Peter Marynen, Lucienne Michaux, Pascal Pierre, Peter VandenbergheAbstract:Chronic Eosinophilic Leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions or other genetic lesions. Most FIP1L1–PDGFRA positive patients enjoy durable and complete molecular responses to low-dose imatinib (Glivec/Gleevec). However, resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease, and sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, is active against this mutant in vitro. We describe a case of FIP1L1-PDGFRα T674I CEL in blast crisis that responded to sorafenib (Nexavar). However, this clinical response was short-lived because of the rapid emergence of a FIP1L1-PDGFRα D842V mutant. An N-Nitroso-N-ethylurea-mutagenesis screen indeed identified this mutant as a major sorafenib-resistant mutant. In vitro, the novel FIP1L1-PDGFRα D842V mutant is highly resistant to sorafenib, imatinib, dasatinib (Sprycell) and PKC412 (Midostaurin). Thus, sorafenib is clinically active in imatinib-resistant FIP1L1-PDGFRα T674I CEL, but the rapid emergence of other mutants may limit the response duration. The identification of new PDGFR inhibitors will be required to overcome resistance by this D842V mutant.
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the eol 1 cell line as an in vitro model for the study of fip1l1 pdgfra positive chronic Eosinophilic Leukemia
Blood, 2004Co-Authors: Jan Cools, Peter Marynen, Hilmar Quentmeier, Brian J. P. Huntly, James D. Griffin, Hans G. Drexler, Gary D GillilandAbstract:We recently identified the chimeric kinase FIP1L1-platelet-derived growth factor receptor α (PDGFRα) as a cause of the hyperEosinophilic syndrome and of chronic Eosinophilic Leukemia. To investigate the role of FIP1L1-PDGFRA in the pathogenesis of acute Leukemia, we screened 87 Leukemia cell lines for the presence of FIP1L1-PDGFRA . One cell line, EOL-1, expressed the FIP1L1-PDGFRA fusion. Three structurally divergent kinase inhibitors—imatinib (STI-571), PKC412, and SU5614—inhibited the growth of EOL-1 cells. These results indicate that the fusion of FIP1L1 to PDGFRA occurs rarely in Leukemia cell lines, but they identify EOL-1 as an in vitro model for the study of FIP1L1-PDGFRA -positive chronic Eosinophilic Leukemia and for the analysis of small molecule inhibitors of FIP1L1-PDGFRα. (Blood. 2004;103:2802-2805)
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The FIP1L1-PDGFRalpha kinase in hyperEosinophilic syndrome and chronic Eosinophilic Leukemia.
Current opinion in hematology, 2004Co-Authors: Iwona Wlodarska, Jan Cools, Elizabeth H Stover, Peter Marynen, D. Gary GillilandAbstract:PURPOSE OF REVIEW The idiopathic hyperEosinophilic syndrome is a rare hematologic disorder characterized by sustained unexplained eosinophilia with associated end-organ damage and by a striking male predominance. The first insights into the molecular etiology of this heterogeneous disease were obtained from a "bedside-to-bench" approach. Successful empiric treatment of patients with the hyperEosinophilic syndrome with the selective tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis) ultimately led to the discovery of the FIP1L1-PDGFRalpha fusion kinase in about half of the hyperEosinophilic syndrome cases. RECENT FINDINGS The FIP1L1-PDGFRA fusion gene is generated by a cryptic interstitial chromosomal deletion, del(4)(q12q12), which indicates that these cases are clonal hematopoietic malignancies and should be reclassified as chronic Eosinophilic Leukemias based on current World Health Organization recommendations. In addition, the FIP1L1-PDGFRA fusion gene was also identified in cases with systemic mast cell disease. In vitro and in vivo studies confirmed that FIP1L1-PDGFRalpha is a therapeutic target of imatinib, forming a rational basis for the treatment of FIP1L1-PDGFRA positive chronic Eosinophilic Leukemia and mastocytosis with imatinib. Similar to BCR-ABL-positive Leukemias, resistance to imatinib due to point mutations in the PDGFRalpha kinase domain may develop. We have explored strategies to circumvent resistance to imatinib using alternative tyrosine kinase inhibitors such as PKC412. SUMMARY The discovery of the FIP1L1-PDGFRA fusion gene in the hyperEosinophilic syndrome is an example of the power of clinical translational research and identifies interstitial chromosomal deletion as a novel mechanism to generate oncogenic tyrosine kinase fusion genes.
Andreas Reiter - One of the best experts on this subject based on the ideXlab platform.
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chronic Eosinophilic Leukemia diagnosis and therapy
Clinical Lymphoma Myeloma & Leukemia, 2021Co-Authors: Jason Gotlib, William Shomali, Andreas ReiterAbstract:Introduction In the 2017 World Health Organization (WHO) classification, chronic Eosinophilic Leukemia, not otherwise specified (CEL, NOS), is included as one of 7 distinct diagnostic entities under the major category of myeloproliferative neoplasms (MPNs).1 WHO defining criteria for CEL, NOS include: (a) peripheral blood eosinophilia >1.5×109/L; (b) evidence of clonal cytogenetic or molecular genetic abnormality, and/or (c) presence of excess myeloblasts (
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Generalized Eruptive Histiocytosis Associated With FIP1L1-PDGFRA-Positive Chronic Eosinophilic Leukemia.
JAMA dermatology, 2015Co-Authors: Birgit Ziegler, Andreas Reiter, Wiebke K. Peitsch, Alexander Marx, Sergij Goerdt, Cyrill GéraudAbstract: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.
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effect of the tyrosine kinase inhibitor nilotinib in patients with hyperEosinophilic syndrome chronic Eosinophilic Leukemia analysis of the phase 2 open label single arm a2101 study
Journal of Cancer Research and Clinical Oncology, 2013Co-Authors: Andreas Hochhaus, Philipp Erben, Andreas Reiter, Hagop M Kantarjian, Philipp Le Coutre, Michele Baccarani, Tracey Mcculloch, Xiaolin Fan, Steven Novick, Francis J GilesAbstract:Purpose HyperEosinophilic syndrome (HES) and chronic Eosinophilic Leukemia (CEL) are characterized by sustained overproduction of eosinophils and organ dysfunction. CEL involves the presence of clonal genetic markers, such as a fusion of FIP1-like 1 protein and platelet-derived growth factor receptor α (FIP1L1-PDGFRα, or F/P) or PDGFRα-activating mutations.
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oncostatin m is a fip1l1 pdgfra dependent mediator of cytokine production in chronic Eosinophilic Leukemia
Allergy, 2013Co-Authors: Gregor Hoermann, Irina Sadovnik, Sabine Cernyreiterer, Leonhard Mullauer, Martin Bilban, Marion Groger, H P Horny, Annette Schmittgraeff, Christine Mannhalter, Andreas ReiterAbstract:Background Chronic Eosinophilic Leukemia (CEL) is a myeloproliferative neoplasm characterized by expansion of neoplastic eosinophils, tissue infiltration, and organ damage. In a subset of these patients, the FIP1L1/PDGFRA (F/P) oncoprotein is detectable. F/P exhibits constitutive tyrosine kinase activity and activates a number of signaling pathways. So far, however, little is known about the role of F/P-dependent proteins in the pathogenesis of CEL. Methods A screen for F/P-dependent cytokines was performed in growth factor-dependent human cell lines lentivirally transduced with F/P. Signal transduction pathways were characterized in Ba/F3 cells with doxycycline-inducible expression of F/P and in EOL-1 cells. Cytokine expression was confirmed in patients' material by immunohistochemistry, immunofluorescence, and confocal microscopy. Gene expression analysis, proliferation assays, and chemotaxis assays were used to elucidate paracrine interactions between neoplastic eosinophils and stromal cells. Results We show that F/P upregulates expression of oncostatin M (OSM) in various cell line models in a STAT5-dependent manner. Correspondingly, neoplastic eosinophils in the bone marrow were found to overexpress OSM. OSM derived from F/P + cells stimulated proliferation of stromal cells. Moreover, OSM-containing supernatants from F/P + cells were found to upregulate production of stromal cell-derived factor-1 (SDF-1)/CXCL12 in human fibroblasts. SDF-1, in turn, induced migration of EOL-1 cells in a dose-dependent manner. Conclusions We have identified a F/P-driven paracrine interaction between neoplastic eosinophils and stromal cells that may contribute to tissue fibrosis and accumulation of neoplastic eosinophils in CEL.
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complete molecular remission of chronic Eosinophilic Leukemia complicated by cns disease after targeted therapy with imatinib
Annals of Hematology, 2004Co-Authors: N Frickhofen, Christoph Walz, Andreas Reiter, Elisabeth Markerhermann, Bernd Jung, Heidi Bauer, Andreas HochhausAbstract:Many cases of hypereosinophilia, formerly classified as hyperEosinophilic syndrome, can now be characterized as chronic Eosinophilic Leukemia (CEL) based on the demonstration of characteristic genetic markers indicating clonality of hematopoiesis. Here we report on a 33-year-old male patient with central nervous system manifestations of CEL and an excellent response to low-dose imatinib (Glivec). Molecular analysis demonstrated a constitutive activation of the platelet-derived growth factor receptor-alpha (PDGFR-A) as the mechanism of responsiveness to imatinib.