title: CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia.
abstract: 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.
authors.affiliation: Inserm, U1016, Institut Cochin, F-75014, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Astori
authors.forename: Hanne
authors.initials: H
authors.lastname: Fredly
authors.forename: Thomas Aquinas
authors.initials: TA
authors.lastname: Aloysius
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Véronique
authors.initials: V
authors.lastname: Mansat-De Mas
authors.forename: Pierre
authors.initials: P
authors.lastname: de la Grange
authors.forename: François
authors.initials: F
authors.lastname: Delhommeau
authors.forename: Karen Marie
authors.initials: KM
authors.lastname: Hagen
authors.forename: Christian
authors.initials: C
authors.lastname: Récher
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusanter-Fourt
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.forename: Johan Richard
authors.initials: JR
authors.lastname: Lillehaug
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pendino
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors
chemical_list: C540448:CXXC5 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors