BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid–dendritic cell leukemia
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.
Authors
- Olivier Armand
- Christopher A.G. Booth (ORCID: https://orcid.org/0000-0003-3841-6637)
- Katsuhiro Togami (ORCID: https://orcid.org/0000-0001-8422-0008)
- Jean‐Pierre Bourquin (ORCID: https://orcid.org/0000-0001-6571-6227)
- Alex Kentsis (ORCID: https://orcid.org/0000-0002-8063-9191)
- Andrew A. Lane (ORCID: https://orcid.org/0000-0001-7380-0226)
- Hembly G. Rivas (ORCID: https://orcid.org/0000-0002-9454-7810)
- Emily M. Lachtara
- Siobhan Rice (ORCID: https://orcid.org/0000-0001-7166-4902)
- Juliette Bouyssou (ORCID: https://orcid.org/0000-0002-2301-0426)
- James A. DeCaprio (ORCID: https://orcid.org/0000-0002-0896-167X)
- Esther Rheinbay (ORCID: https://orcid.org/0000-0002-5566-6729)
- Kezhi Yan (ORCID: https://orcid.org/0000-0002-2964-0963)
- Shuyuan Cheng (ORCID: https://orcid.org/0000-0003-0746-509X)
Institutions
- Broad Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Cornell University (US)
- Harvard University Press (US)
- Kettering University (US)
- Dana-Farber Cancer Institute (US)
- University Children's Hospital Zurich (CH)
- Center for Cancer Research (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-11-05
- DOI
- https://doi.org/10.1172/jci.insight.183889
- Citations
- 7
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 3.07
Funders
- U.S. Department of Defense
- Leukemia and Lymphoma Society
- Mark Foundation For Cancer Research
- EMBO
- National Institutes of Health
- Ludwig Center at Harvard
- National Cancer Institute