BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid-dendritic cell leukemia.

Autor: Booth CA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Bouyssou JM; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Togami K; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Armand O; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Rivas HG; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.; Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA., Yan K; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Rice S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Cheng S; Tow Center for Developmental Oncology, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Molecular Pharmacology Program, Sloan Kettering Institute, New York, New York, USA.; Departments of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Medical College of Cornell University, New York, New York, USA., Lachtara EM; Krantz Family Center for Cancer Research, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., Bourquin JP; Division of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland., Kentsis A; Tow Center for Developmental Oncology, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.; Molecular Pharmacology Program, Sloan Kettering Institute, New York, New York, USA.; Departments of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Medical College of Cornell University, New York, New York, USA., Rheinbay E; Krantz Family Center for Cancer Research, Boston, Massachusetts, USA.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA., DeCaprio JA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA., Lane AA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 Dec 20; Vol. 9 (24). Date of Electronic Publication: 2024 Dec 20.
DOI: 10.1172/jci.insight.183889
Abstrakt: 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.
Databáze: MEDLINE