Blood Journal
Leading the way in experimental and clinical research in hematology

CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia

  1. Megan E. McNerney1,
  2. Christopher D. Brown2,
  3. Xiaoyue Wang2,
  4. Elizabeth T. Bartom3,
  5. Subhradip Karmakar1,
  6. Chaitanya Bandlamudi4,
  7. Shan Yu1,
  8. Jinkyung Ko5,
  9. Barry P. Sandall5,
  10. Thomas Stricker6,
  11. John Anastasi7,
  12. Robert L. Grossman1,
  13. John M. Cunningham5,
  14. Michelle M. Le Beau8, and
  15. Kevin P. White1,*
  1. 1 Institute for Genomics and Systems Biology, University of Chicago, Chicago, IL, United States;
  2. 2 Department of Human Genetics, University of Chicago, Chicago, IL, United States;
  3. 3 Center for Research Informatics, University of Chicago, Chicago, IL, United States;
  4. 4 Committee on Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, IL, United States;
  5. 5 Department of Pediatrics, Section of Hematology/Oncology and Stem Cell Transplantation, University of Chicago, Chicago, IL, United States;
  6. 6 Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States;
  7. 7 Department of Pathology, University of Chicago, Chicago, IL, United States;
  8. 8 Section of Hematology/Oncology, University of Chicago, Chicago, IL, United States
  1. * Corresponding author; email: kpwhite{at}uchicago.edu

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 one case, CUX1 was disrupted by a translocation resulting in a loss-of-function RNA fusion transcript. http://submit.bloodjournal.org/tracking/download?roleName=staff&msid=BLOOD/2012/426965&fullms=true&queueName=pap_queuewas 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 upon 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.

  • Submitted April 30, 2012.
  • Accepted November 4, 2012.