| First Author | Nguyen N | Year | 2022 |
| Journal | iScience | Volume | 25 |
| Issue | 1 | Pages | 103679 |
| PubMed ID | 35036869 | Mgi Jnum | J:327739 |
| Mgi Id | MGI:6856476 | Doi | 10.1016/j.isci.2021.103679 |
| Citation | Nguyen N, et al. (2022) Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation. iScience 25(1):103679 |
| abstractText | Abnormal activation of SETBP1 due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of Hoxa9/Hoxa10/Myb transcription by SETBP1 and its missense mutants is essential for their transforming capability; however, the underlying epigenetic mechanisms remain elusive. We found that both SETBP1 and its missense mutant SETBP1(D/N) directly interact with histone methyltransferase MLL1. Using a combination of ChIP-seq and RNA-seq analysis in primary hematopoietic stem and progenitor cells, we uncovered extensive overlap in their genomic occupancy and their cooperation in activating many oncogenic transcription factor genes including Hoxa9/Hoxa10/Myb and a large group of ribosomal protein genes. Genetic ablation of Mll1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated Setbp1/Setbp1(D/N)-induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in Setbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation. |
