NKL homeobox gene activities in hematopoietic stem cells, T-cell development and T-cell leukemia

• Published in: PloS one Vol. 12; no. 2; p. e0171164
• Main Authors: Nagel, Stefan, Pommerenke, Claudia, Scherr, Michaela, Meyer, Corinna, Kaufmann, Maren, Battmer, Karin, MacLeod, Roderick A. F., Drexler, Hans G.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.02.2017; Public Library of Science (PLoS)
• Subjects: Aberration; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Apoptosis; Apoptosis - genetics; Biology and Life Sciences; Cancer; CD34 antigen; Cell culture; Cell Differentiation - genetics; Cell Line, Tumor; Cells (biology); Cells, Cultured; Deregulation; Ectopic expression; Gene expression; Gene Expression Profiling; Gene regulation; Gene Regulatory Networks; Genes; Genes, Homeobox; Genetic aspects; Hematology; Hematopoiesis; Hematopoiesis - genetics; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Homeobox; Homeodomain Proteins - genetics; Humans; Leukemia; Lymphatic leukemia; Lymphocytes T; Lymphoma; Lymphopoiesis; Lymphopoiesis - genetics; Medicine and Health Sciences; Microorganisms; MSX1 Transcription Factor - genetics; Nkx2.3 protein; Nkx2.5 protein; Physiology; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Progenitor cells; Proteins; Stem cells; T cell receptors; T cells; T-Lymphocytes - cytology; T-Lymphocytes - metabolism; Thyroid transcription factor 1; Tlx1 protein; Tlx3 protein; Transcription; Transcription Factors - genetics; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0171164

T-cell acute lymphoblastic leukemia (T-ALL) cells represent developmentally arrested T-cell progenitors, subsets of which aberrantly express homeobox genes of the NKL subclass, including TLX1, TLX3, NKX2-1, NKX2-5, NKX3-1 and MSX1. Here, we analyzed the transcriptional landscape of all 48 members of the NKL homeobox gene subclass in CD34+ hematopoietic stem and progenitor cells (HSPCs) and during lymphopoiesis, identifying activities of nine particular genes. Four of these were expressed in HSPCs (HHEX, HLX1, NKX2-3 and NKX3-1) and three in common lymphoid progenitors (HHEX, HLX1 and MSX1). Interestingly, our data indicated downregulation of NKL homeobox gene transcripts in late progenitors and mature T-cells, a phenomenon which might explain the oncogenic impact of this group of genes in T-ALL. Using MSX1-expressing T-ALL cell lines as models, we showed that HHEX activates while HLX1, NKX2-3 and NKX3-1 repress MSX1 transcription, demonstrating the mutual regulation and differential activities of these homeobox genes. Analysis of a public T-ALL expression profiling data set comprising 117 patient samples identified 20 aberrantly activated members of the NKL subclass, extending the number of known NKL homeobox oncogene candidates. While 7/20 genes were also active during hematopoiesis, the remaining 13 showed ectopic expression. Finally, comparative analyses of T-ALL patient and cell line profiling data of NKL-positive and NKL-negative samples indicated absence of shared target genes but instead highlighted deregulation of apoptosis as common oncogenic effect. Taken together, we present a comprehensive survey of NKL homeobox genes in early hematopoiesis, T-cell development and T-ALL, showing that these genes generate an NKL-code for the diverse stages of lymphoid development which might be fundamental for regular differentiation.