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

McNerney ME, Brown CD, Wang X, Bartom ET, Karmakar S, Bandlamudi C, Yu S, Ko J, Sandall BP, Stricker T, Anastasi J, Grossman RL, Cunningham JM, Le Beau MM, White KP
Blood. 2013 121 (6): 975-83

PMID: 23212519 · PMCID: PMC3567344 · DOI:10.1182/blood-2012-04-426965

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.

MeSH Terms (27)

Acute Disease Animals Blotting, Western Cell Line, Tumor Chromosome Deletion Chromosomes, Human, Pair 7 Drosophila melanogaster Gene Expression Profiling Haploinsufficiency HeLa Cells Homeodomain Proteins Humans Interleukin Receptor Common gamma Subunit K562 Cells Leukemia, Myeloid Mice Mice, Inbred NOD Mice, Knockout Mice, SCID Nuclear Proteins Repressor Proteins Reverse Transcriptase Polymerase Chain Reaction RNA Interference Translocation, Genetic Tumor Suppressor Proteins U937 Cells Xenograft Model Antitumor Assays

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