NKL homeobox gene activities in B-cell development and lymphomas

• Published in: PloS one Vol. 13; no. 10; p. e0205537
• Main Authors: Nagel, Stefan, MacLeod, Roderick A. F., Meyer, Corinna, Kaufmann, Maren, Drexler, Hans G.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 11.10.2018; Public Library of Science (PLoS)
• Subjects: B-cell lymphoma; Biology and Life Sciences; Biotechnology; Bone morphogenetic protein 7; Cancer; Care and treatment; Cell culture; Cell differentiation; Chromatin; Chromosome 8; Chromosome rearrangements; Datasets; Deregulation; Development and progression; Differentiation (biology); DNA binding proteins; Embryos; Gene expression; Genes; Genetic aspects; Genetic transformation; Health aspects; Hematopoiesis; Hematopoietic stem cells; Hemopoiesis; Homeobox; Immunological memory; Leukemia; Leukemogenesis; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphoma; Lymphomas; Lymphopoiesis; Mantle cell lymphoma; Medicine and Health Sciences; Memory cells; Microorganisms; Nkx2.2 protein; Pax5 protein; Physiology; Plasma cells; Stem cells; T cells; Thyroid transcription factor 1; Transcription (Genetics); Transcription activation; Transcription factors; Transformation; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0205537

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.