Research Article: NKL homeobox gene activities in B-cell development and lymphomas

Date Published: October 11, 2018

Publisher: Public Library of Science

Author(s): Stefan Nagel, Roderick A. F. MacLeod, Corinna Meyer, Maren Kaufmann, Hans G. Drexler, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0205537

Abstract

Homeobox genes encode transcription factors which regulate basic processes in development and cell differentiation. Several members of the NKL subclass are deregulated in T-cell progenitors and support leukemogenesis. We have recently described particular expression patterns of nine NKL homeobox genes in early hematopoiesis and T-cell development. Here, we screened NKL homeobox gene activities in normal B-cell development and extended the NKL-code to include this lymphoid lineage. Analysis of public expression profiling datasets revealed that HHEX and NKX6-3 were the only members differentially active in naïve B-cells, germinal center B-cells, plasma cells and memory B-cells. Subsequent examination of different types of B-cell malignancies showed both aberrant overexpression of NKL-code members and ectopic activation of subclass members physiologically silent in lymphopoiesis including BARX2, DLX1, EMX2, NKX2-1, NKX2-2 and NKX3-2. Based on these findings we performed detailed studies of the B-cell specific NKL homeobox gene NKX6-3 which showed enhanced activity in patient subsets of follicular lymphoma, mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL), and in three DLBCL cell lines to serve as in vitro models. While excluding genomic and chromosomal rearrangements at the locus of NKX6-3 (8p11) promoter studies demonstrated that B-cell factors MYB and PAX5 activated NKX6-3 transcription. Furthermore, aberrant BMP7/SMAD1-signalling and deregulated expression of chromatin complex components AUTS2 and PCGF5 promoted NKX6-3 activation. Finally, NKL homeobox genes HHEX, HLX, MSX1 and NKX6-3 were expressed in B-cell progenitors and generated a regulatory gene network in cell lines which we propose may provide physiological support for NKL-code formation in early B-cell development. Together, we identified an NKL-code in B-cell development whose violation may deregulate differentiation and promote malignant transformation.

Partial Text

Hematopoietic stem cells (HSCs) generate common myeloid and lymphoid progenitor (CMP/CLP) cells which, respectively, initiate the differentiation into myeloid and lymphoid cell lineages. The latter produces all types of lymphocytes comprising B-cells, T-cells, and NK-cells. Early B-cell development begins with the B-cell progenitor (BCP) and takes place in the bone marrow. The final differentiation steps to memory B-cells and plasma cells via naïve and germinal center (GC) B-cells occur in lymph nodes and in the spleen [1–3]. Lymphopoiesis including B-cell development is regulated mainly at the transcriptional level [3,4]. Accordingly, several transcription factors (TFs) including PAX5, MYB, BCL6 and PRDM1/BLIMP1 generate a B-cell specific regulatory network controlling fundamental differentiation processes [5,6]. Deregulation of these TFs by chromosomal rearrangement or gene mutation contributes to the generation of B-cell malignancies [7,8].

In this study we analyzed physiological activities of NKL homeobox genes in B-cell development. Considered together with previously published data, this examination detected expression patterns which complete the NKL-code for early hematopoiesis and lymphopoiesis (Fig 1). Additional results of our work are summarized in Fig 8, which shows a gene regulatory network surrounding NKL homeobox gene NKX6-3. TFs MYB and PAX5, BMP7/SMAD1-signalling, and PRC1.5-mediator AUTS2 all activate expression of NKX6-3.

 

Source:

http://doi.org/10.1371/journal.pone.0205537

 

0 0 vote
Article Rating
Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments