BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid–dendritic cell leukemia Journal Article
| Authors: | Booth, C. A. G.; Bouyssou, J. M.; Togami, K.; Armand, O.; Rivas, H. G.; Yan, K.; Rice, S.; Cheng, S.; Lachtara, E. M.; Bourquin, J. P.; Kentsis, A.; Rheinbay, E.; DeCaprio, J. A.; Lane, A. A. |
| Article Title: | BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid–dendritic cell leukemia |
| Abstract: | MYB fusions are recurrently found in select cancers, including blastic plasmacytoid DC neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared with other blood cancers and, in some patients, are the only obvious somatic mutation detected. This suggests that they may alone be sufficient to drive DC transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but, mechanistically, how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that, in BPDCN leukemogenesis, MYB switches from being a regulator of DC lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in patients with BPDCN increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired DC differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN. © 2024, Booth et al. |
| Keywords: | controlled study; survival rate; gene mutation; human cell; somatic mutation; nonhuman; flow cytometry; animal cell; mouse; animal tissue; cell cycle; gene overexpression; gene expression; dendritic cell; animal experiment; animal model; cell differentiation; immunofluorescence; carcinogenesis; escherichia coli; western blotting; enzyme linked immunospot assay; oncogene c myb; t lymphocyte activation; rna sequence; human; article; blastic plasmacytoid dendritic cell neoplasm |
| Journal Title: | JCI Insight |
| Volume: | 9 |
| Issue: | 24 |
| ISSN: | 2379-3708 |
| Publisher: | Amer Soc Clinical Investigation Inc |
| Date Published: | 2024-12-20 |
| Start Page: | e183889 |
| Language: | English |
| DOI: | 10.1172/jci.insight.183889 |
| PUBMED: | 39499902 |
| PROVIDER: | scopus |
| PMCID: | PMC11665559 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF -- Source: Scopus |
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