-7/del(7q) is prevalent across subtypes of myeloid neoplasms. CUX1, located on 7q22, encodes a homeodomain-containing transcription factor, and, like -7/del(7q), CUX1 inactivating mutations independently carry a poor prognosis. As with loss of 7q, CUX1 mutations often occur early in disease pathogenesis. We reported that CUX1 deficiency causes myelodysplastic syndrome in mice but was insufficient to drive acute myeloid leukemia (AML). Given the known association between -7/del(7q) and RAS pathway mutations, we mined cancer genome databases and explicitly linked CUX1 mutations with oncogenic RAS mutations. To determine if activated RAS and CUX1 deficiency promote leukemogenesis, we generated mice bearing NrasG12D and CUX1-knockdown which developed AML, not seen in mice with either mutation alone. Oncogenic RAS imparts increased self-renewal on CUX1-deficient hematopoietic stem/progenitor cells (HSPCs). Reciprocally, CUX1 knockdown amplifies RAS signaling through reduction of negative regulators of RAS/PI3K signaling. Double mutant HSPCs were responsive to PIK3 or MEK inhibition. Similarly, low expression of CUX1 in primary AML samples correlates with sensitivity to the same inhibitors, suggesting a potential therapy for malignancies with CUX1 inactivation. This work demonstrates an unexpected convergence of an oncogene and tumor suppressor gene on the same pathway.
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The datasets generated during the current study are available in the GEO repository, accession GSE161614.
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The authors are grateful for the services and assistance provided by the following University of Chicago core facilities supported by the Cancer Center Support Grant (P30 CA014599): Integrated Light Microscopy Core, Cytometry and Antibody Technology Core (RRID: SCR_017760), Human Tissue Resource Center (RRID: SCR_019199), and the Genomics Facility (RRID: SCR_019196). We also thank The University of Chicago’s Center for Research Informatics Bioinformatics Core and Animal Resources Center. We thank Dr. Jeffrey Klco (St. Jude Children’s Research Hospital) for providing the lentiviral plasmids. We also gratefully acknowledge Dr. Angela Stoddart for critical reading of the manuscript. The authors would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing. Interpretations are the responsibility of the study authors.
This work was supported in part by the American Cancer Society Research Scholar Grant 132457-RSG-18-171-01-LIB, American Society of Hematology Junior Faculty Scholar Award, the National Institutes of Health (R01 HL142782 and R01 CA231880), the Brinson Foundation, and The University of Chicago Cancer Research Foundation Women’s Board. MKI is supported by NIH F30 CA232673 and The University of Chicago Medical Scientist Training Program (T32 GM007281). The authors gratefully acknowledge the support of Robin and Matthew Patinkin.
The authors declare no competing interests.
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An, N., Khan, S., Imgruet, M.K. et al. Oncogenic RAS promotes leukemic transformation of CUX1-deficient cells. Oncogene 42, 881–893 (2023). https://doi.org/10.1038/s41388-023-02612-x