CXXC5 (Retinoid-Inducible Nuclear Factor, RINF) is a Potential Therapeutic Target in High-Risk Human Acute Myeloid Leukemia
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Audrey Astori1,2,3, Hanne Fredly4,5, Thomas Aquinas Aloysius6, Lars Bullinger7, Véronique Mansat-De Mas8,9, Pierre de la Grange10, François Delhommeau11,12, Karen Marie Hagen4,5, Christian Récher8,9, Isabelle Dusanter-Fourt1,2,3, Stian Knappskog6, Johan Richard Lillehaug6, Frédéric Pendino*,1,2,3,6, Øystein Bruserud*,4,5
1 Inserm, U1016, Institut Cochin, F-75014, Paris, France;
2 CNRS, UMR8104, F-75014, Paris, France;
3 Université Paris Descartes, Sorbonne Paris Cité, Paris, France;
4 Section for Hematology, Institute of Medicine, University of Bergen, Norway;
5 Department of Medicine, Haukeland University Hospital; Bergen, Norway;
6 Department of Molecular Biology, University of Bergen, Bergen, Norway;
7 Department of Internal Medicine III, University of Ulm, Ulm, Germany;
8 Inserm, Unité Mixte de Recherche 1037-Cancer Research Center of Toulouse, CNRS 5294, Université de Toulouse, Centre Hospitalier Universitaire Purpan, F-31059, Toulouse, France;
9 Service d’Hématologie, Centre Hospitalier Universitaire Purpan, Hôpital Purpan, F-31059, Toulouse, France;
10 GenoSplice, Hôpital Saint-Louis, F-75010, Paris, France;
11 UPMC, Pierre and Marie Curie University, GRC n°07, Groupe de Recherche Clinique sur les Myéloproliférations Aiguës et Chroniques MyPAC, F-75012, Paris, France;
12 AP-HP, Hôpital Saint-Antoine, Service d’Hématologie et Immunologie Biologiques, F-75012, Paris, France.
* These two authors shared the last authorship.
Frédéric Pendino, email:
Keywords: Acute myeloid leukemia, CXXC5/RINF, chemotherapy, apoptosis
Received: July 30, 2013 Accepted: August 13, 2013 Published: August 15, 2013
The retinoid-responsive gene CXXC5 localizes to the 5q31.2 chromosomal region and encodes a retinoid-inducible nuclear factor (RINF) that seems important during normal myelopoiesis. We investigated CXXC5/RINF expression in primary human acute myeloid leukemia (AML) cells derived from 594 patients, and a wide variation in CXXC5/RINF mRNA levels was observed both in the immature leukemic myeloblasts and in immature acute lymphoblastic leukemia cells. Furthermore, patients with low-risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML. This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML. CXXC5/RINF knockdown in AML cell lines caused increased susceptibility to chemotherapy-induced apoptosis, and regulation of apoptosis also seemed to differ between primary human AML cells with high and low RINF expression. The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells.
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