ETV6-PDGFRB and FIP1L1-PDGFRA Stimulate Human Hematopoietic Progenitor Cell Proliferation and Differentiation into Eosinophils: the Role of Nuclear Factor-κB

Overview

Journal Haematologica

Specialty Hematology

Date 2012 Jan 25

PMID 22271894

Citations 21

Authors

Carmen P Montano-Almendras

Ahmed Essaghir

Helene Schoemans

Inci Varis

Laura A Noel

Amelie I Velghe

Dominique Latinne

Laurent Knoops

Jean-Baptiste Demoulin

Affiliations

Soon will be listed here.

Abstract

Background: ETV6-PDGFRB (also called TEL-PDGFRB) and FIP1L1-PDGFRA are receptor-tyrosine kinase fusion genes that cause chronic myeloid malignancies associated with hypereosinophilia. The aim of this work was to gain insight into the mechanisms whereby fusion genes affect human hematopoietic cells and in particular the eosinophil lineage.

Design And Methods: We introduced ETV6-PDGFRB and FIP1L1-PDGFRA into human CD34(+) hematopoietic progenitor and stem cells isolated from umbilical cord blood.

Results: Cells transduced with these oncogenes formed hematopoietic colonies even in the absence of cytokines. Both oncogenes also stimulated the proliferation of cells in liquid culture and their differentiation into eosinophils. This model thus recapitulated key features of the myeloid neoplasms induced by ETV6-PDGFRB and FIP1L1-PDGFRA. We next showed that both fusion genes activated the transcription factors STAT1, STAT3, STAT5 and nuclear factor-κB. Phosphatidylinositol-3 kinase inhibition blocked nuclear factor-κB activation in transduced progenitor cells and patients' cells. Nuclear factor-κB was also activated in the human FIP1L1-PDGFRA-positive leukemia cell line EOL1, the proliferation of which was blocked by bortezomib and the IκB kinase inhibitor BMS-345541. A mutant IκB that prevents nuclear translocation of nuclear factor-κB inhibited cell growth and the expression of eosinophil markers, such as the interleukin-5 receptor and eosinophil peroxidase, in progenitors transduced with ETV6-PDGFRB. In addition, several potential regulators of this process, including HES6, MYC and FOXO3 were identified using expression microarrays.

Conclusions: We show that human CD34(+) cells expressing PDGFR fusion oncogenes proliferate autonomously and differentiate towards the eosinophil lineage in a process that requires nuclear factor-κB. These results suggest new treatment possibilities for imatinib-resistant myeloid neoplasms associated with PDGFR mutations.

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References

Cools J, DeAngelo D, Gotlib J, Stover E, Legare R, Cortes J . 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. DOI: 10.1056/NEJMoa025217. View

Fujihara S, Ward C, Dransfield I, Hay R, Uings I, Hayes B . Inhibition of nuclear factor-kappaB activation un-masks the ability of TNF-alpha to induce human eosinophil apoptosis. Eur J Immunol. 2002; 32(2):457-66. DOI: 10.1002/1521-4141(200202)32:2<457::AID-IMMU457>3.0.CO;2-1. View

Biffi A, Bartolomae C, Cesana D, Cartier N, Aubourg P, Ranzani M . Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood. 2011; 117(20):5332-9. DOI: 10.1182/blood-2010-09-306761. View

Reiter A, Walz C, Watmore A, Schoch C, Blau I, Schlegelberger B . The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res. 2005; 65(7):2662-7. DOI: 10.1158/0008-5472.CAN-04-4263. View

Medves S, Noel L, Montano-Almendras C, Albu R, Schoemans H, Constantinescu S . Multiple oligomerization domains of KANK1-PDGFRβ are required for JAK2-independent hematopoietic cell proliferation and signaling via STAT5 and ERK. Haematologica. 2011; 96(10):1406-14. PMC: 3186300. DOI: 10.3324/haematol.2011.040147. View

Rauch B, Weber A, Braun M, Zimmermann N, Schror K . PDGF-induced Akt phosphorylation does not activate NF-kappa B in human vascular smooth muscle cells and fibroblasts. FEBS Lett. 2000; 481(1):3-7. DOI: 10.1016/s0014-5793(00)01957-8. View

Vu H, Xinh P, Masuda M, Motoji T, Toyoda A, Sakaki Y . FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation. Leukemia. 2006; 20(8):1414-21. DOI: 10.1038/sj.leu.2404266. View

Sunwoo J, Chen Z, Dong G, Yeh N, Crowl Bancroft C, Sausville E . Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res. 2001; 7(5):1419-28. View

Guzman M, Neering S, Upchurch D, Grimes B, Howard D, Rizzieri D . Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001; 98(8):2301-7. DOI: 10.1182/blood.v98.8.2301. View

10.

Tefferi A, Levine R, Lim K, Abdel-Wahab O, Lasho T, Patel J . Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia. 2009; 23(5):900-4. PMC: 4654631. DOI: 10.1038/leu.2009.37. View

11.

Essaghir A, Dif N, Marbehant C, Coffer P, Demoulin J . The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. J Biol Chem. 2009; 284(16):10334-42. PMC: 2667720. DOI: 10.1074/jbc.M808848200. View

12.

Kallin A, Johannessen L, Cani P, Marbehant C, Essaghir A, Foufelle F . SREBP-1 regulates the expression of heme oxygenase 1 and the phosphatidylinositol-3 kinase regulatory subunit p55 gamma. J Lipid Res. 2007; 48(7):1628-36. DOI: 10.1194/jlr.M700136-JLR200. View

13.

Medves S, Duhoux F, Ferrant A, Toffalini F, Ameye G, Libouton J . KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia. Leukemia. 2010; 24(5):1052-5. DOI: 10.1038/leu.2010.13. View

14.

BESANCON F, Atfi A, Gespach C, Cayre Y, Bourgeade M . Evidence for a role of NF-kappaB in the survival of hematopoietic cells mediated by interleukin 3 and the oncogenic TEL/platelet-derived growth factor receptor beta fusion protein. Proc Natl Acad Sci U S A. 1998; 95(14):8081-6. PMC: 20932. DOI: 10.1073/pnas.95.14.8081. View

15.

Carroll M, Tomasson M, Barker G, Golub T, Gilliland D . The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta R kinase-dependent signaling pathways. Proc Natl Acad Sci U S A. 1996; 93(25):14845-50. PMC: 26224. DOI: 10.1073/pnas.93.25.14845. View

16.

Toffalini F, Demoulin J . New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases. Blood. 2010; 116(14):2429-37. DOI: 10.1182/blood-2010-04-279752. View

17.

Cools J, Quentmeier H, Huntly B, Marynen P, Griffin J, Drexler H . The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood. 2003; 103(7):2802-5. DOI: 10.1182/blood-2003-07-2479. View

18.

Gratton M, Torban E, Jasmin S, Theriault F, German M, Stifani S . Hes6 promotes cortical neurogenesis and inhibits Hes1 transcription repression activity by multiple mechanisms. Mol Cell Biol. 2003; 23(19):6922-35. PMC: 193938. DOI: 10.1128/MCB.23.19.6922-6935.2003. View

19.

Temple R, Allen E, Fordham J, Phipps S, Schneider H, Lindauer K . Microarray analysis of eosinophils reveals a number of candidate survival and apoptosis genes. Am J Respir Cell Mol Biol. 2001; 25(4):425-33. DOI: 10.1165/ajrcmb.25.4.4456. View

20.

PRESENTEY B, Jerushalmy Z, Mintz U . Eosinophilic leukaemia: morphological, cytochemical, and electron microscopic studies. J Clin Pathol. 1979; 32(3):261-71. PMC: 1145633. DOI: 10.1136/jcp.32.3.261. View