Normal and Aberrant TALE-Class Homeobox Gene Activities in Pro-B-Cells and B-Cell Precursor Acute Lymphoblastic Leukemia

Abstract

Homeobox genes encode transcription factors regulating basic developmental processes. They are arranged according to sequence similarities of their conserved homeobox in 11 classes, including TALE. Recently, we have reported the so-called TALE-code. This gene signature describes physiological expression patterns of all active TALE-class homeobox genes in the course of hematopoiesis. The TALE-code allows the evaluation of deregulated TALE homeobox genes in leukemia/lymphoma. Here, we extended the TALE-code to include the stages of pro-B-cells and pre-B-cells in early B-cell development. Detailed analysis of the complete lineage of B-cell differentiation revealed expression of TALE homeobox genes IRX1 and MEIS1 exclusively in pro-B-cells. Furthermore, we identified aberrant expression of IRX2, IRX3 and MEIS1 in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) which originates from early B-cell progenitors. The data showed correlated activities of deregulated TALE-class members with particular BCP-ALL subtype markers, namely IRX2 with TCF3/E2A-fusions, IRX3 with ETV6/TEL-fusions, and MEIS1 with KMT2A/MLL-fusions. These correlations were also detected in BCP-ALL cell lines which served as experimental models. We performed siRNA-mediated knockdown experiments and reporter gene assays to analyze regulatory connections. The results showed mutual activation of IRX1 and TCF3. In contrast, IRX2 directly repressed wild-type TCF3 while the fusion gene TCF3::PBX1 lost the binding site for IRX2 and remained unaltered. IRX3 mutually activated fusion gene ETV6::RUNX1 while activating itself by aberrantly expressed transcription factor KLF15. Finally, KMT2A activated MEIS1 which in turn supported the expression of IRX3. In summary, we revealed normal TALE homeobox gene expression in early B-cell development and identified aberrant activities of IRX2, IRX3 and MEIS1 in particular subtypes of BCP-ALL. Thus, these TALE homeobox genes may serve as novel diagnostic markers and therapeutic targets.

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

“…In previous studies, we have proposed several types of TF-code, detailing gene signatures for selected TF groups in the hematopoietic compartment. Examples include the NKL- and TALE-codes, which cover NKL-subclass and TALE-class homeobox gene activities for each progenitor and mature immune cell entity [ 7 , 9 , 10 ]. In line with these previously published codes, we here describe the myeloid CUT-code, covering CUT-class homeobox gene activities in developing and mature myeloid cell types.…”

“…To evaluate their role in normal and aberrant lymphoid and myeloid immune and blood cell development, we previously identified so-called “TF-codes”. These codes describe physiological activities of TALE-class or NKL-subclass homeobox genes, for example, in developing and mature hematopoietic entities, and hence are named “TALE-code” or “NKL-code” [ 7 , 9 , 10 ]. These benchmark gene signatures illuminate our understanding of regulatory processes in the hematopoietic compartment and enable rapid identification of deregulated homeobox genes in corresponding malignancies [ 7 , 9 , 10 ].…”

“…These codes describe physiological activities of TALE-class or NKL-subclass homeobox genes, for example, in developing and mature hematopoietic entities, and hence are named "TALE-code" or "NKL-code" [7,9,10]. These benchmark gene signatures illuminate our understanding of regulatory processes in the hematopoietic compartment and enable rapid identification of deregulated homeobox genes in corresponding malignancies [7,9,10]. Dendritic cells (DCs) are myeloid immune cells which sense and capture bacteria or virus-infected cells and subsequently display specific antigens to T-cells prior to eliciting immune responses [11].…”

Bioinformatics for Wet-lab Scientists: Practical Application in Sequencing Analysis

“…Indeed, in recent years an increasing number of researchers have integrated their own results with public datasets and used bioinformatic tools in their analysis similar to what we proposed in this review. This includes such broad applications as cellular senescence [97], carcinogenesis [98,99], or immunology [100,101]. Still, this approach necessitates a reciprocal reflection of the object of inquiry and the methodology used, and questions such as the following should therefore be asked: What kind of data are available and which data might be lacking to complement the picture?…”

Aberrant stem cell and developmental programs in pediatric leukemia

“…In AML, IRX1/3/5 is aberrantly expressed ( Nagel and Meyer, 2022 ). In AML cell lines, expressions of IRX1 and IRX3/5 are mutually exclusive with opposing effects on GATA1/2 activity ( Somerville et al, 2018 ).…”