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    Functional characterization of RINF (alias CXXC5) in normal and pathological hematopoiesis

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    Principal Investigator

    Contact: frederic.pendino@inserm.fr Tel: +33 1 40 51 64 03

     

    Scientific background

     

    In 2009, we have identified (by a microarray screening approach) the previously uncharacterized CXXC5 gene sequence [1]. This gene encodes a nuclear factor that we have renamed RINF for Retinoid-Inducible Nuclear Factor. Our in vitro functional studies have demonstrated its essential role during maturation of normal hematopoietic cells [1, 2], and chemotherapeutic resistance of leukemic cells [3, 4]. We have also investigated the status of this gene in large cohorts of patients suffering from leukemia and cancer. RINF expression is deregulated in leukemia [3, 4], solid tumors [5], and constitutes a promising prognostic marker [6-7] as well as a challenging therapeutic target [3, 4].

     

     

    At the molecular level, RINF protein contains a CXXC zinc finger domain that is almost identical to the one harbored by TET1, TET3, as well CXXC4 (an inhibitor of TET2), three epigenetic modulators suggested to be involved in the erasure of DNA-methylation marks. Thus, RINF could interfere with TET-activities and genome-wide CpG hydroxymethylation. This epigenetic activity could explain, at least partly, its functional participation to maturation of various blood and immune cells as well as malignant transformation and therapeutic resistance of tumor cells.

     

     

    Objectives

     

    By using gain and loss-of-function experiments in normal hematopoietic stem cells and progenitors, leukemic cell lines, primary cells from patients, and animal models, our main research activities concerning RINF are focusing on its putative role during:

    • Erythropoiesis (Research Theme 1),
    • Stem cell renewal (Research Theme 2),
    • Therapeutic response of leukemic cells (Research Theme 3)
    • Epigenetics regulation

    At the molecular level, the mode of action of RINF protein is investigated by the identification of its binding partners (immunoprecipitation coupled with mass spectrometry) and putative target genes (ChIP-seq, genome-wide analysis of gene expression analysis by using microarrays, bioinformatics…).

     

    Members of team involved on RINF theme

     

    Present members:
            Frédéric Pendino (Research Scientist, Ph.D., CR1 Inserm).
            Gabriel Matherat (Ph.D. student, Paris Descartes University).
            Aurelia Alimi (Master student level 2, Pediatrician specialized in Onco-Hematology)

    Previous members:
             Megane Le Brech (Undergraduate Student, Summer 2016)
            Audrey Astori (Ph.D. Thesis defended in December 2014)
            Amir Kadi (Postdoctoral fellow until 2014)
            Hélène Babski (Master student level 1, until 2014)

     

     

    References

     

    [1] Pendino F, Nguyen E, Jonassen I, Dysvik B, Azouz A, Lanotte M, Ségal-Bendirdjian E, Lillehaug JR. Functional involvement of RINF, retinoid-inducible nuclear factor (CXXC5), in normal and tumoral human myelopoiesis. Blood. 2009 Apr 2;113(14):3172-81.

    [2]  Astori A, Feuillet V, Gautier EF, Masserot C, Kadi A, Le Bon A, Nguyen E, Zermati Y, Verdier F, Lauret E, Bruserud Ø, Lillehaug JE, Ségal-Bendirdjian E, Dusanter-Fourt I, Mayeux P, and Pendino F. RINF (alias CXXC5) expression favors granulopoiesis and impairs erythropoiesis of human hematopoietic progenitors. Manuscript In Preparation.

    [3]  Astori A, Fredly H, Aloysius TA, Bullinger L, Mansat-De Mas V, de la Grange P, Delhommeau F, Hagen KM, Récher C, Dusanter-Fourt I, Knappskog S, Lillehaug JR, Pendino F (Corr. Auth.), Bruserud Ø. CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia.  Oncotarget. 2013. Sep;4(9):1438-48.

    [4]  Bruserud Ø, Reikvam H, Fredly H, Skavland J, Hagen KM, van Hoang TT, Brenner AK, Kadi A, Astori A, Gjertsen BT, Pendino F. Expression of the potential therapeutic target CXXC5 in primary acute myeloid leukemia cells - high expression is associated with adverse prognosis as well as altered intracellular signaling and transcriptional regulation. Oncotarget. 2015. Feb 20;6(5):2794-2811.

    [5] Knappskog S, Myklebust LM, Busch C, Aloysius T, Varhaug JE, Lønning PE, Lillehaug JR, Pendino F. RINF (CXXC5) is overexpressed in solid tumors and is an unfavorable prognostic factor in breast cancer. Annals of Oncology. 2011. 22(10).2208-15.

    [6] PCT application WO 2010/085153.

    [7] PCT application WO 2012/010661 A.

    [8] Ko M et al. Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX. Nature, 2013. 497(7447).122-6.

     

    Support and funding

     

    The project received research grants from Ligue National Contre le Cancer and a support from AURORA-exchange program (PHC, collaboration with University of Bergen, Norway). Some translational aspects of the research project are supported by SATT-idf-innov, Cochin Institute, and Inserm-Transfert.