Transcriptional Landscape of CUT-Class Homeobox Genes in Blastic Plasmacytoid Dendritic Cell Neoplasm

Homeobox genes encode developmental transcription factors regulating tissue-specific differentiation processes and drive cancerogenesis when deregulated. Dendritic cells (DCs) are myeloid immune cells occurring as two types, either conventional or plasmacytoid DCs. Recently, we showed that the expre...

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Bibliographic Details
Published in:International journal of molecular sciences 2024-02, Vol.25 (5), p.2764
Main Authors: Nagel, Stefan, Rand, Ulfert, Pommerenke, Claudia, Meyer, Corinna
Format: Article
Language:English
Subjects:
ALCL
AML
Binding sites
Biomarkers
Blood
Cell Differentiation
Cell Line
CUT-code
Datasets
Dendritic cells
Dendritic Cells - metabolism
DNA binding proteins
Gene expression
Genes
Genes, Homeobox
Genetic aspects
Genetic transcription
Genomes
Health aspects
Hematologic Neoplasms - pathology
homeodomain
Homeodomain Proteins - genetics
HOXA9
Humans
Leukemia
Lymphoma
Myeloid Cells - metabolism
NKL-code
Physiology
Proteins
RNA
Transcription Factors - metabolism
Tumors
Citations: Items that this one cites
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Summary:Homeobox genes encode developmental transcription factors regulating tissue-specific differentiation processes and drive cancerogenesis when deregulated. Dendritic cells (DCs) are myeloid immune cells occurring as two types, either conventional or plasmacytoid DCs. Recently, we showed that the expression of NKL-subclass homeobox gene VENTX is restricted to conventional DCs, regulating developmental genes. Here, we identified and investigated homeobox genes specifically expressed in plasmacytoid DCs (pDCs) and derived blastic plasmacytoid dendritic cell neoplasm (BPDCN). We analyzed gene expression data, performed RQ-PCR, protein analyses by Western blot and immuno-cytology, siRNA-mediated knockdown assays and subsequent RNA-sequencing and live-cell imaging. Screening of public gene expression data revealed restricted activity of the CUT-class homeobox gene CUX2 in pDCs. An extended analysis of this homeobox gene class in myelopoiesis showed that additional CUX2 activity was restricted to myeloid progenitors, while BPDCN patients aberrantly expressed ONECUT2, which remained silent in the complete myeloid compartment. ONECUT2 expressing BPDCN cell line CAL-1 served as a model to investigate its regulation and oncogenic activity. The ONECUT2 locus at 18q21 was duplicated and activated by IRF4, AUTS2 and TNF-signaling and repressed by BMP4-, TGFb- and IL13-signalling. Functional analyses of ONECUT2 revealed the inhibition of pDC differentiation and of CDKN1C and CASP1 expression, while SMAD3 and EPAS1 were activated. EPAS1 in turn enhanced survival under hypoxic conditions which thus may support dendritic tumor cells residing in hypoxic skin lesions. Collectively, we revealed physiological and aberrant activities of CUT-class homeobox genes in myelopoiesis including pDCs and in BPDCN, respectively. Our data may aid in the diagnosis of BPDCN patients and reveal novel therapeutic targets for this fatal malignancy.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms25052764