PMID- 38474011 OWN - NLM STAT- MEDLINE DCOM- 20240314 LR - 20240315 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 25 IP - 5 DP - 2024 Feb 27 TI - Transcriptional Landscape of CUT-Class Homeobox Genes in Blastic Plasmacytoid Dendritic Cell Neoplasm. LID - 10.3390/ijms25052764 [doi] LID - 2764 AB - 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. FAU - Nagel, Stefan AU - Nagel S AUID- ORCID: 0000-0003-4431-8988 AD - Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, 38124 Braunschweig, Germany. FAU - Rand, Ulfert AU - Rand U AUID- ORCID: 0000-0002-5946-4921 AD - Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, 38124 Braunschweig, Germany. FAU - Pommerenke, Claudia AU - Pommerenke C AUID- ORCID: 0000-0002-9448-416X AD - Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, 38124 Braunschweig, Germany. FAU - Meyer, Corinna AU - Meyer C AD - Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, 38124 Braunschweig, Germany. LA - eng PT - Journal Article DEP - 20240227 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (ONECUT2 protein, human) RN - 0 (Transcription Factors) RN - 0 (Homeodomain Proteins) SB - IM MH - Humans MH - *Genes, Homeobox MH - Cell Differentiation MH - Cell Line MH - Myeloid Cells/metabolism MH - Dendritic Cells/metabolism MH - *Hematologic Neoplasms/pathology MH - Transcription Factors/metabolism MH - Homeodomain Proteins/genetics PMC - PMC10932245 OTO - NOTNLM OT - ALCL OT - AML OT - CUT-code OT - HOXA9 OT - NKL-code OT - ZHX2 OT - homeodomain OT - pyroptosis COIS- The authors declare no conflicts of interest. EDAT- 2024/03/13 06:46 MHDA- 2024/03/14 06:47 PMCR- 2024/02/27 CRDT- 2024/03/13 01:23 PHST- 2024/01/15 00:00 [received] PHST- 2024/02/20 00:00 [revised] PHST- 2024/02/23 00:00 [accepted] PHST- 2024/03/14 06:47 [medline] PHST- 2024/03/13 06:46 [pubmed] PHST- 2024/03/13 01:23 [entrez] PHST- 2024/02/27 00:00 [pmc-release] AID - ijms25052764 [pii] AID - ijms-25-02764 [pii] AID - 10.3390/ijms25052764 [doi] PST - epublish SO - Int J Mol Sci. 2024 Feb 27;25(5):2764. doi: 10.3390/ijms25052764.