Extensive planting of crops genetically engineered to produce insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) has suppressed some major pests, reduced insecticide sprays, enhanced pest control by natural enemies, and increased grower profits. However, rapid evolution of resistance in pests is reducing these benefits. Better understanding of the genetic basis of resistance to Bt crops is urgently needed to monitor, delay, and counter pest resistance. We discovered that a point mutation in a previously unknown tetraspanin gene in the cotton bollworm (Helicoverpa armigera), a devastating global pest, confers dominant resistance to Cry1Ac, the sole Bt protein produced by transgenic cotton planted in China. We found the mutation using a genome-wide association study, followed by fine-scale genetic mapping and DNA sequence comparisons between resistant and susceptible strains. CRISPR/Cas9 knockout of the tetraspanin gene restored susceptibility to a resistant strain, whereas inserting the mutation conferred 125-fold resistance in a susceptible strain. DNA screening of moths captured from 23 field sites in six provinces of northern China revealed a 100-fold increase in the frequency of this mutation, from 0.001 in 2006 to 0.10 in 2016. The correspondence between the observed trajectory of the mutation and the trajectory predicted from simulation modeling shows that the dominance of the mutation accelerated adaptation. Proactive identification and tracking of the tetraspanin mutation demonstrate the potential for genomic analysis, gene editing, and molecular monitoring to improve management of resistance.
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.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. (Blood. 2013;121(6):975-983)
IntroductionLoss of chromosome 7 and del(7q) [Ϫ7/del(7q)] was first recognized as a frequent event in acute myeloid leukemia (AML) nearly 40 years ago. 1 Ϫ7/del(7q) occurs in 8% of de novo AML 2 and 50% of therapy-related myeloid neoplasms (t-MNs). 3 Ϫ7/del(7q) is also found in myelodysplastic syndromes, AMLs arising from myeloproliferative neoplasms, the blast phase of chronic myelogenous leukemia, Ph ϩ acute lymphoblastic leukemia, and AMLs associated with inherited syndromes. 4-10 Ϫ7/del(7q) is an adverserisk prognostic indicator in myeloid disorders, and the long-term outcome for patients is typically poor. The median overall survival for patients with de novo AML or t-MNs with Ϫ7/del(7q) is ϳ 6 months. 2,3 Loss of 1 or more tumor suppressor gene(s) (TSGs) is thought to contribute to leukemic growth in myeloid malignancies with Ϫ7/del(7q). Several groups have mapped a commonly deleted segment (CDS) of chromosome band 7q22 using polymorphic markers, conventional cytogenetic analysis, and FISH analysis. [11][12][13] In one study of 81 patients with malignant myeloid disorders characterized by chromosome 7 abnormalities, the CDS was mapped to a 2.52-Mb region of 7q22 by FISH using YAC clones. 11 However, deletion ...
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