Abstract
Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation and are grouped into classes and subclasses according to sequence similarities. Here, we analyzed the activities of the 20 members strong TALE homeobox gene class in early hematopoiesis and in lymphopoiesis including developing and mature B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells (ILC). The resultant expression pattern comprised eleven genes and which we termed TALE-code enables discrimination of normal and aberrant activities of TALE homeobox genes in lymphoid malignancies. Subsequent expression analysis of TALE homeobox genes in public datasets of Hodgkin lymphoma (HL) patients revealed overexpression of IRX3, IRX4, MEIS1, MEIS3, PBX1, PBX4 and TGIF1. As paradigm we focused on PBX1 which was deregulated in about 17% HL patients. Normal PBX1 expression was restricted to hematopoietic stem cells and progenitors of T-cells and ILCs but absent in B-cells, reflecting its roles in stemness and early differentiation. HL cell line SUP-HD1 expressed enhanced PBX1 levels and served as an in vitro model to identify upstream regulators and downstream targets in this malignancy. Genomic studies of this cell line therein showed a gain of the PBX1 locus at 1q23 which may underlie its aberrant expression. Comparative expression profiling analyses of HL patients and cell lines followed by knockdown experiments revealed NFIB and TLX2 as target genes activated by PBX1. HOX proteins operate as cofactors of PBX1. Accordingly, our data showed that HOXB9 overexpressed in HL coactivated TLX2 but not NFIB while activating TNFRSF9 without PBX1. Further downstream analyses showed that TLX2 activated TBX15 which operated anti-apoptotically. Taken together, we discovered a lymphoid TALE-code and identified an aberrant network around deregulated TALE homeobox gene PBX1 which may disturb B-cell differentiation in HL by reactivation of progenitor-specific genes. These findings may provide the framework for future studies to exploit possible vulnerabilities of malignant cells in therapeutic scenarios.
Highlights
To produce the complete panel of blood and immune cells hematopoiesis begins with hematopoietic stem cells (HSCs) in the bone marrow
Reduction of RYBP by siRNA-mediated knockdown in SUP-HD1 resulted in elevated TLX2 expression levels while that of PBX1 remained unchanged (Fig 5C). These results indicated that this repressor mediates inhibition of NKL homeobox gene TLX2 but not of TALE homeobox gene PBX1
This code epitomizes physiological gene expressions for 11 of 20 described TALE homeobox genes and serves as tool for identification and evaluation of deregulated class members in lymphoid malignancies. These data demonstrate PBX1 activity in hematopoietic stem and progenitor cells and correspond to reports showing that PBX1 regulates self renewal and lineage choice in HSCs and myeloid and lymphoid compartments [38,39]
Summary
To produce the complete panel of blood and immune cells hematopoiesis begins with hematopoietic stem cells (HSCs) in the bone marrow. HSCs and lymphomyeloid-primed progenitors (LMPP) generate common myeloid progenitors (CMP) and common lymphoid progenitors (CLP). CMPs initiate the differentiation into all myeloid cells while CLPs produce all types of lymphocytes comprising B-cells, T-cells, natural killer (NK)-cells and innate lymphoid cells (ILC). Several transcription factors (TFs) like BCL6, EBF1, NKX6-3 and PAX5 generate a B-cell specific regulatory network controlling basic differentiation processes [4,5,6]. Deregulation of these TFs by chromosomal rearrangement, gene mutation or Epstein-Barr virus infection underlies the generation of B-cell malignancies [7,8,9]. The analysis of particular developmental TFs may illuminate our understanding of both normal lymphopoiesis and lymphoid neoplasms
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