title: CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia.
abstract: Loss of chromosome 7 and del(7q) [-7/del(7q)] are recurring cytogenetic abnormalities in hematologic malignancies, including acute myeloid leukemia and therapy-related myeloid neoplasms, and associated with an adverse prognosis. Despite intensive effort by many laboratories, the putative myeloid tumor suppressor(s) on chromosome 7 has not yet been identified.We performed transcriptome sequencing and SNP array analysis on de novo and therapy-related myeloid neoplasms, half with -7/del(7q). We identified a 2.17-Mb commonly deleted segment on chromosome band 7q22.1 containing CUX1, a gene encoding a homeodomain-containing transcription factor. In 1 case, CUX1 was disrupted by a translocation, resulting in a loss-of-function RNA fusion transcript. CUX1 was the most significantly differentially expressed gene within the commonly deleted segment and was expressed at haploinsufficient levels in -7/del(7q) leukemias. Haploinsufficiency of the highly conserved ortholog, cut, led to hemocyte overgrowth and tumor formation in Drosophila melanogaster. Similarly, haploinsufficiency of CUX1 gave human hematopoietic cells a significant engraftment advantage on transplantation into immunodeficient mice. Within the RNA-sequencing data, we identified a CUX1-associated cell cycle transcriptional gene signature, suggesting that CUX1 exerts tumor suppressor activity by regulating proliferative genes. These data identify CUX1 as a conserved, haploinsufficient tumor suppressor frequently deleted in myeloid neoplasms.
authors.affiliation: Institute for Genomics and Systems Biology, Department of Pathology, University of Chicago, IL 60637, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: McNerney
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Brown
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Wang
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Bartom
authors.forename: Subhradip
authors.initials: S
authors.lastname: Karmakar
authors.forename: Chaitanya
authors.initials: C
authors.lastname: Bandlamudi
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.forename: Jinkyung
authors.initials: J
authors.lastname: Ko
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sandall
authors.forename: Thomas
authors.initials: T
authors.lastname: Stricker
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.forename: Robert L
authors.initials: RL
authors.lastname: Grossman
authors.forename: John M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Kevin P
authors.initials: KP
authors.lastname: White
mesh_terms: D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D020869:Gene Expression Profiling; D057895:Haploinsufficiency; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D053631:Interleukin Receptor Common gamma Subunit; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins