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

Megan E. McNerney*, Christopher D. Brown, Xiaoyue Wang, Elizabeth T. Bartom, Subhradip Karmakar, Chaitanya Bandlamudi, Shan Yu, Jinkyung Ko, Barry P. Sandall, Thomas Stricker, John Anastasi, Robert L. Grossman, John M. Cunningham, Michelle M. Le Beau, Kevin P. White

*Corresponding author for this work

Research output: Contribution to journalArticle

82 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)975-983
Number of pages9
JournalBlood
Volume121
Issue number6
DOIs
StatePublished - Feb 7 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

McNerney, M. E., Brown, C. D., Wang, X., Bartom, E. T., Karmakar, S., Bandlamudi, C., Yu, S., Ko, J., Sandall, B. P., Stricker, T., Anastasi, J., Grossman, R. L., Cunningham, J. M., Le Beau, M. M., & White, K. P. (2013). CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. Blood, 121(6), 975-983. https://doi.org/10.1182/blood-2012-04-426965