Abstract
Multiple myeloma is a hematological cancer of plasma B cells and remains incurable. Two major subtypes of myeloma, hyperdiploid MM (HMM) and non-hyperdiploid MM (NHMM), have distinct chromosomal alterations and different survival outcomes. Transcription factors (TrFs) have been implicated in myeloma oncogenesis, but their dysregulation in myeloma subtypes are less studied. Here, we developed a TrF-pathway coexpression analysis to identify altered coexpression between two sample types. We apply the method to the two myeloma subtypes and the cell cycle arrest pathway, which is significantly differentially expressed between the two subtypes. We find that TrFs MYC, nuclear factor-κB and HOXA9 have significantly lower coexpression with cell cycle arrest in HMM, co-occurring with their overactivation in HMM. In contrast, TrFs ESR1 (estrogen receptor 1), SP1 and E2F1 have significantly lower coexpression with cell cycle arrest in NHMM. SP1 chromatin immunoprecipitation targets are enriched by cell cycle arrest genes. These results motivate a cooperation model of ESR1 and SP1 in regulating cell cycle arrest, and a hypothesis that their overactivation in NHMM disrupts proper regulation of cell cycle arrest. Cotargeting ESR1 and SP1 shows a synergistic effect on inhibiting myeloma proliferation in NHMM cell lines. Therefore, studying TrF-pathway coexpression dysregulation in human cancers facilitates forming novel hypotheses toward clinical utility.
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Acknowledgements
This work was supported by National Basic Research Program of China (973 Program; No. 2010CB944904) (XW, YL, YZ, CL) and NIH R01 GM077122 (CL, ZY). This work was also supported in part by NIH Grants RO1-124929, PO1-155258, P50-100007 and PO1-78378 (to NCM) and by the Department of Veterans Affairs Merit Review Awards (to NCM). PKS was supported by Claudia Adams Barr Program in Innovative Basic Cancer Research and the Multiple Myeloma Career Development award. We thank the reviewers and Cheng Li group members for constructive comments and discussion.
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XW, ZY and CL designed the study. XW implemented the methodology, analyzed the data and interpreted the results in the context of biological literature. YL predicted the HMM status of one data set. PKS, SBA and YZ contributed to study design and data analysis. MF, MG and NCM provided biological interpretation of the results and carried out drug treatment experiments. XW and CL wrote the manuscript. All authors reviewed and approved the manuscript.
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Wang, X., Yan, Z., Fulciniti, M. et al. Transcription factor-pathway coexpression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma. Leukemia 28, 894–903 (2014). https://doi.org/10.1038/leu.2013.233
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DOI: https://doi.org/10.1038/leu.2013.233
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