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,
  2. Christopher D. Brown1,3,
  3. Xiaoyue Wang1,3,
  4. Elizabeth T. Bartom4,
  5. Subhradip Karmakar1,
  6. Chaitanya Bandlamudi1,5,
  7. Shan Yu1,5,
  8. Jinkyung Ko6,
  9. Barry P. Sandall6,
  10. Thomas Stricker7,
  11. John Anastasi2,
  12. Robert L. Grossman1,4,
  13. John M. Cunningham6,
  14. Michelle M. Le Beau1,8, and
  15. Kevin P. White1,3,9
  1. 1Institute for Genomics and Systems Biology,
  2. 2Department of Pathology,
  3. 3Department of Human Genetics,
  4. 4Center for Research Informatics,
  5. 5Committee on Genetics, Genomics, and Systems Biology, and
  6. 6Department of Pediatrics, Section of Hematology/Oncology and Stem Cell Transplantation, University of Chicago, Chicago, IL;
  7. 7Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN; and
  8. Sections of 8Hematology/Oncology and
  9. 9Genetic Medicine, University of Chicago, Chicago, IL

Key Points

  • CUX1 is a transcription factor encoded on a region of chromosome 7 that is frequently deleted in high-risk acute myeloid leukemia.

  • Haploinsufficiency of CUX1/cut promotes hematopoietic overgrowth in both Drosophila melanogaster and human xenograft mouse models in vivo.

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.

  • Submitted April 27, 2012.
  • Accepted November 4, 2012.
View Full Text